ABSTRACT: This 6-year prospective follow-up study evaluated the rate ofclinical disease progression in 19 of 20 previously reported patients withstrictly selected limb girdle muscular dystrophy. There was no significantdeterioration in muscle strength (assessed by manual muscle testing). Anactivities of daily living (ADL) scale showed significant functional deteriorationin 30% of patients with predominant involvement in a single functional domainvariable between patients, and determined by the patient’s previous level offunction. A functional grading system showed that 70% of patients haddeteriorated at least one grade in the arms and/or legs. Deterioration of theADL score correlated with the loss of functional grades. We conclude thatassessment of functional ability may be more sensitive to detect clinicaldisease progression compared to testing of muscle strength. The clinicalparameter that correlates best with the activity of the underlying diseaseprocess is not determined. Tests for strength and functional impairment arecomplementary. Patients expressed appreciation that functional disabilitywas addressed during follow-up visits. 1997 John Wiley & Sons, Inc. MuscleNerve, 20, 453–460, 1997.Key words: limb girdle muscular dystrophy; manual muscle testing; activitiesof daily living; functional grading; clinical disease progression

LIMB GIRDLE MUSCULARDYSTROPHY: A PROSPECTIVEFOLLOW-UP STUDY OFFUNCTIONAL IMPAIRMENT

JOERG-PATRICK STUBGEN, MB ChB, MMed(Neuro), FCP(SA), FRCP(C),

MD(Pret)1* and ANNETTE STIPP, B Arb(Pret)2

1 Department of Neurology (A-569), Cornell University Medical College, 525 East68th Street, New York, New York 10021, USA2 Lynn Med Clinic, Pretoria, South Africa

Received 20 June 1996; accepted 31 October 1996

date, at least five autosomal recessive LGMDs haveThe clinical syndrome of progressive limb girdlebeen identified. In LGMD 2A, a mutation has beenand proximal limb muscle weakness has a diverseidentified on chromosome 15 in the gene of theetiology.4,18 These limb girdle syndromes remain dif-nonstructural protein calpain, a calcium-activatedficult to understand and classify. Included is a smallprotease.8,17 LGMD 2B is localized to the short armgroup of primary myopathies with progressive limbof chromosome 2 (2p13–p16)2; the gene and genegirdle weakness, commonly familial, with myopatho-product have not yet been identified. The sarcogly-logical features that suggest a dystrophic process.canopathies are due to mutations in the genes encod-Molecular genetic studies confirm the clinical im-ing for dystrophin-associated glycoproteins. LGMDpression that limb girdle muscular dystrophy2C (previously, severe congenital autosomal recessive(LGMD) is not a single disease. There are at leastmuscular dystrophy, SCARMD), is the result of muta-two genes for autosomal dominant LGMD; the genetions in the gamma-sarcoglycan gene on chromo-for LGMD 1A is localized on chromosome 5q,19,27 andsome 13 (13q12).15 LGMD 2D, also known as ad-LGMD 1B has as yet no assigned chromosome.20 Tohalinopathy or alpha-sarcoglycanopathy, is due tomutations in the adhalin gene on chromosome 17(17q12–q21.33).16 LGMD 2E has been associatedwith mutations in the beta-sarcoglycan gene on*Correspondence to: Dr. J.-P. Stubgen

Contract grant sponsor: This study was supported in part by the Phyllis chromsome 4 (4q12).3

Knocker-Bradlow Award for 1991 from The College of Medicine of South Manual muscle testing is an established, reliableAfrica, and the Lasker Education Foundation.method to evaluate strength in neuromuscular andCCC 0148-639X/97/040453-08

1997 John Wiley & Sons, Inc. other nervous system diseases.13 Inter- and intraob-

Limb Girdle Muscular Dystrophy MUSCLE & NERVE April 1997 453

server inconsistencies and lack of sensitivity have not a. The inheritance pattern: autosomal recessivein six families [more than one sibling affecteddetracted from its widespread use at the bedside.

However, patients are more concerned with, and in- in five families (9 patients) and one consan-guineous marriage (1 patient)], and 10 spo-terested in, progressive worsening or loss of function.

Functional testing of the arms and legs assigns radic cases. (The younger sister of a previouslyreported sporadic male patient developedpatients a functional grade.14 This evaluation is easy

to use, inexpensive, and reproducible. Applied at LGMD during the 6-year interval but did notpartake in this reevaluation.)intervals over time, this test reflects the clinical course

of disease. An activities of daily living (ADL) scale, b. The phenotype has been described in detail21:all patients were weak in a symmetrical limbmeanwhile, assesses disability across multiple func-

tional domains. An evaluation can be based on self- girdle and proximal limb distribution in vari-ous degrees of severity without facial involve-report by patients or on performance of required

tasks in a simulated home environment. Numerous ment (Fig. 1). Distal limb muscles were mildlyweak, and always stronger than proximal mus-functional tests have been devised to evaluate and

characterize the natural history of neuromuscular cles. Mild joint contractures were detected inchronically wheelchair-bound patients, but diddiseases.1,24,25 However, an evaluation based on prob-

lem specificity rather than disease specificity is clini- not affect significantly the range of motion ofany joint or limb.cally more relevant.5 It is not established how these

clinical indices of disease progression correlate with c. Electromyography was consistent with an ac-tive, chronic myopathy.22the activity of the underlying neuromuscular dis-

ease process. d. Muscle histopathology showed dystrophic le-sions (nonspecific, degenerative, and regener-We recently reported a cross-sectional and retro-

spective study on 20 patients with LGMD in which ative changes with whorled and necrotic fi-bers) in all biopsies. The absence of anprogressive weakness was compared to functional dis-

ability.23 We determined that: (1) for any functional inflammatory cell infiltrate, ragged red fibers,features of congenital or metabolic myopa-grade the degree of weakness varied between pa-

tients; (2) the functional level predictably deterio- thies, and chronic neurogenic changes ex-cluded other causes of limb girdle weakness.rated at threshold weakness; (3) change in functional

grade was not reflected in a parallel increase in weak-ness; and (4) functional milestones were reached at In addition, a normal dystrophin staining pattern

(immune peroxidase precipitation technique) in 4varying durations of disease.In this follow-up study stretching over 6 years, we male patients (3 sporadic and 1 familial case) likely

excluded Duchenne and Becker muscular dystro-wanted to: (1) prospectively monitor progression ofweakness by manual muscle testing to determine phies.whether the rate of progression in this homogeneousgroup of patients was consistent at variable ages, de- Access to Previous Results. In order to avoid un-

conscious duplication of results which could havegree of weakness, or disease duration; (2) prospec-tively monitor functional impairment at variable age, influenced findings, access to previous information

in patient charts was avoided until after completiondegree of weakness, or disease duration; (3) deter-mine whether particular ADL functions are suscepti- of the reevaluation of all the patients.ble to progressive weakness or disease; and (4) estab-lish whether an impression of functional Manual Muscle Testing. To reassess muscle strength

manually, a modification of the British Medical Re-deterioration and, possibly, disease activity gainedfrom a retrospective analysis of patient history is com- search Council (MRC) scale was chosen.13 Quantifi-

cation of global muscle strength was obtained by test-parable to a prospective evaluation using the same in-dices. ing movements around the neck, shoulders, elbows,

wrists, hips, knees, and ankles; 17 muscle groups onboth sides were examined. For purpose of analysis,

METHODS the MRC scale was converted to a 0–10-point system:0 5 0; 1 5 1; 2 5 2; 32 5 3; 3 5 4; 31 5 5; 42, 4,Patients. Nineteen of 20 patients with LGMD pre-

viously described were reevaluated after a 6-year inter- and 41 5 7; 52 5 9; 5 5 10. The average musclescore (AMS) is the numerical average of 34 musclesval. Controversies surround the definition of

LGMD,26 and patients were selected according to the tested. Of a possible maximum of 10, the lower thescore, the weaker the patient.following criteria:

454 Limb Girdle Muscular Dystrophy MUSCLE & NERVE April 1997

FIGURE 1. The LGMD phenotype: note wasting of deltoid, forearm flexor, thigh adductor, and medial head of the gastrocnemius muscles.

Functional Grade. All patients were reassigned a patients in 1989/1990 and 1996. Statistical signifi-cance was set at P , 0.05.functional grade based on a scale proposed by Vignos

et al.25 and modified by Brooke et al.6 (Table 1).

RESULTSActivities of Daily Living (ADL) Scale. A 39-item in-

Nineteen of 20 patients (12 females, 7 males) wereventory was completed again on each patient basedreevaluated. The mean age at disease onset was 21.1on self-report and observation in a simulated homeyears (range 12–60 years) and the mean age wasenvironment.9,10,12 The questionnaire contained items47.2 years (range 28–73 years), and the mean diseaserepresenting the following functional domains: bedduration was 25.2 years (range 12–48 years).mobility (2 items); wheelchair mobility (9 items);

walking and climbing mobility (6 items); standing upand sitting down (5 items): self-care (13 items); and Strength (AMS). The results of the global strength‘‘miscellaneous’’ (4 items). Each item was scored on evaluation (AMS) for 1989/1990 and 1996 are pre-a 0–4 scale with higher scores indicating greater func- sented in bar form in Figure 2. For the patient grouptional impairment: 0 5 not applicable; 1 5 indepen- as a whole, the decrease in strength over the 6-yeardent; 2 5 manages with minimal assistance; 3 5 needs period was not statistically significant (P 5 0.97). Inmaximal assistance; 4 5 totally dependent. Scores 7 patients, the AMS was lower, in 10 patients the AMSwere obtained for each domain by summing contrib- was higher, and in 2 patients the AMS was unchangeduting items. A total ADL disability score was obtained in 1996 compared to 1989/1990. The variation inby summing scores across all items. change of muscle strength was not related to the

degree of weakness, disease duration, or age of thepatient. Subgroup analysis showed that for neitherStatistical Analysis. The T-square test was used to

compare the means of the AMS and ADL scores of the 6 strongest nor 6 weakest patients was there a

Limb Girdle Muscular Dystrophy MUSCLE & NERVE April 1997 455

significant change in strength (P 5 0.47 and 0.71, re-Table 1. Functional grading.spectively).

Arms1. Starting with arms at sides, patient can abduct arms in Activities of Daily Living (ADL). The results of the

full circle until they touch above head. Can place atotal ADL scores for 1989/1990 and 1996 are pre-weight .0.5 kg on a shelf above eye level.sented in bar form in Figure 3. For the patient group2. Can raise arms above head as above; cannot place 0.5

kg weight on shelf. as a whole, the increase in the total ADL score (mean-3. Can raise arms above head only by flexing elbow/use ing functionally more impaired) was not statistically

of accessory muscles. significant (P 5 0.49). Thirteen patients had higher4. Cannot raise hands above head; can raise glass of

ADL scores and 6 patients had lower ADL scores. Ofwater to mouth.the 6 most functionally impaired patients (1989/5. Cannot raise hands to mouth; can use hands to hold

pen/pick coins from table. 1990), 5 patients worsened; the degree of deteriora-6. Cannot raise hands to mouth and has no useful hand tion was statistically insignificant (P 5 0.26), but func-

function. tionally significant. Of the 6 functionally least im-Legs

paired patients (1989/1990), 3 patients worsened;1. Walks and climbs stairs without assistance.the degree of deterioration was not statistically sig-2. Walks and climbs stairs with aid of railing.

3. Walks and climbs stairs slowly with aid; .12s for 4 nificant (P 5 0.59). A clinically meaningful deteriora-standard steps. tion in functional ability could be ascribed to a single

4. Walks unassisted and rises from chair; cannot climb functional domain in 7 patients: 3 patients becamestairs.

more or less wheelchair-dependent; in 1 patient a5. Walks unassisted; cannot rise from chair; cannot climbdecrease in wheelchair mobility was the chief reasonstairs.

6. Walks with assistance or independently with leg braces. for functional impairment, and in 1 patient walking7. Walks in leg braces but requires assistance for and climbing mobility was the chief reason for func-

balance. tional deterioration. In 2 chronic wheelchair-bound8. Stands in leg braces; unable to walk even with

patients, self-care abilities deteriorated significantly.assistance.However, in 1 patient deterioration in global impair-9. Is in a wheelchair.

10. Confined to bed. ment (deduced from an increase in the total ADLscore) was only apparent; a wheelchair-bound patientcould, with maximal assistance, perform some walk-

FIGURE 2. Bars represent the results of the global muscle strength evaluation for patients in 1989/1990 and 1996. AMS, averagemuscle score. Disease duration in years by 1996 reevaluation. M, male; F, female.

456 Limb Girdle Muscular Dystrophy MUSCLE & NERVE April 1997

FIGURE 3. Bars represent the total score of the activities of daily living (ADL) evaluation of patients in 1989/1990 and 1996. Diseaseduration in years by 1996 reevaluation. M, male; F, female.

ing and climbing functions which she had not been functional milestones, if applicable. The shortcom-ings of such an approach are the retrospective natureable to do during the previous evaluation [herof such a study, and the reliance on patient memorywalking/climbing mobility score jumped from 0 (notwith doubts about accuracy. With this report, weapplicable) to 24].wanted to complement such a retrospective analysiswith prospective data. To what extent the rate ofFunctional Grading. Results of the functional grad-progression of weakness and functional decline cor-ing for arms and legs are given in Table 2. Withinrelates with activity of the underlying muscle diseasethe 6 years of observation, the functional grade hadhas not been definitely established. However, patientsdeteriorated in the arms in 10 patients, and in theare more concerned with, and interested in, progres-legs in 11 patients. In 7 patients, arms and legs hadsive worsening or loss of function. Although LGMDdeteriorated at least one grade; in 3 patients the armsis regarded as a relatively benign progressive muscleonly deteriorated by one grade, and in 4 patients thedisease stretching over many decades and with a nor-legs only deteriorated by one grade. Three patientsmal life expectancy,4,18 the interval analysis had shownhad within the last 6 years made use of a wheelchairthat for the patient group as a whole deteriorationon occasions. Deterioration by one functional gradein functional grades had taken place at regular inter-was not obviously correlated with patient age, diseasevals of between 1 and 4 years. Whether the range induration, or the degree of global muscle weakness.the rate of functional decline represented differentFurthermore, in 6 patients functional deteriorationdystrophic illnesses cannot be answered, as separateof arms and/or legs was associated with a clinicallydisease entities were not clinically recognized11; mo-significant deterioration in the total ADL score.lecular genetic studies are in progress. With this back-ground, we did not regard a 6-year time interval as

DISCUSSION too short to obtain potentially significant data in aIn a recently published cross-sectional and retrospec- prospective manner.

Although manual muscle testing is regarded astive study on a homogeneous group of 20 patientswith LGMD, we determined the progression of func- the standard objective bedside tool to clinically evalu-

ate progression of muscle disease, it is not establishedtional impairment by an interval analysis.23 Patientshad been asked to recall from memory how long that this is the most appropriate or relevant method.

Manual muscle testing is not a very sensitive index,after disease onset they had reached predetermined

Limb Girdle Muscular Dystrophy MUSCLE & NERVE April 1997 457

Table 2. Functional grading.

Arms Legs

Disease Functional Age grade Last grade Functional Age grade Last gradeAge duration AMS grade reached change grade reached change

72 12 8.8 1 72 — 2 66 628 14 4.4 4 26 2 4(9) 25 330 16 2.6 5 17 13 9 17 1332 16 4.8 4 29 3 5 27 546 16 8.5 1 46 — 2 40 630 18 — — — — — — —40 19 8.3 1 40 — 2 30 1058 21 8.5 2 57 1 6 57 138 21 4.8 2 38 0 9 38 038 21 7.4 4 35 3 6(9) 34 456 23 8.5 1 56 — 6 54 240 24 6.8 1 40 — 2 38 242 25 5.1 3 37 5 6(9) 37 552 28 8.6 2 48 4 2 45 746 30 4.7 5 41 5 9 41 549 35 4.4 4 42 7 9 42 755 36 2.8 5 43 12 9 38 1752 37 2.9 5 41 11 9 45 750 37 3.6 5 45 5 9 42 873 48 3.0 6 67 6 9 60 13

Ages, disease duration, and grade changes are in years. AMS, average muscle score.

and in this study patients had noticed increased exer- Any improvement (i.e., numerically lower) inADL score was neither numerically nor clinically sig-tion and ‘‘fatigue,’’ and decreased exercise tolerance

with little or no objective evidence of progressive nificant. Closer analysis revealed that the only patientwith some functionally relevant improvement was aweakness. Although the AMS was higher in half the

patients we examined after the 6-year interval, this young woman, previously wheelchair-bound, who onreevaluation could stand and walk with maximal assis-apparent improvement in global strength was numer-

ically significant (set at greater than about 5% of the tance from her husband-to-be. Her follow-up ADLscore showed a ‘‘false’’ deterioration in function. Ad-total score6) in only 3 patients. The higher AMS on

repeat examination, even if not significant in most aptation and increased motivation probably playeda role.cases, may have been due to: (1) observer inconsis-

tency—this was not the explanation. The strength In 6 patients a clinically significant deteriorationin function occurred. The AMS in these patients wasevaluation of a given muscle did not differ by more

than one consecutive step, when the highest rating insignificantly changed. One interpretation is thatan assessment of functional ability over multiple do-was strength 2 or more.7 (2) The selection criteria

were strict, and it is unlikely that patients with a spon- mains is more sensitive than manual muscle testingto detect clinical disease progression. Furthermore,taneously improving (no patients were placed on

treatment) myopathy were included in this study. (3) there was no apparent correlation of functional dete-rioration with patient age or disease duration. MajorIncreased motivation may have played a role; one

young woman was about to be married (the future deterioration in function was mostly restricted to asingle functional domain, and was determined by thehusband watched in on the examination), and 2

women had changed their ‘‘attitude’’ toward the dis- patients’ previous level of function. Three patientsbecame more or less dependent on a wheelchair;ease (lost weight and partook in a physical therapy

program). (4) Adaptation to weakness is unlikely to one permanently and 2 others more and less than50% of the time, respectively. The ‘‘threshold’’ weak-have played a role in what is a simple objective bed-

side test of strength. (5) Lastly, the improvement in ness in 2 patients was at an AMS score just under 5,and agreed with our retrospective analysis study. Thethe AMS may have been real (i.e., due to increased

tensile strength), implying that muscle fiber recovery patient who only at times made use of a wheelchairsuffered predominantly hip flexion weakness not re-or regeneration outstripped degeneration.

458 Limb Girdle Muscular Dystrophy MUSCLE & NERVE April 1997

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