Nadine A. M. E. van der Beek

Modifying the Medical Research Council grading system through Rasch analyses

The Medical Research Council grading system has served through decades for the evaluation of muscle strength and has been recognized as a cardinal feature of daily neurological, rehabilitation and general medicine examination of patients, despite being respectfully criticized due to the unequal width of its response options. No study has systematically examined, through modern psychometric approach, whether physicians are able to properly use the Medical Research Council grades. The objectives of this study were: (i) to investigate physicians’ ability to discriminate among the Medical Research Council categories in patients with different neuromuscular disorders and with various degrees of weakness through thresholds examination using Rasch analysis as a modern psychometric method; (ii) to examine possible factors influencing physicians’ ability to apply the Medical Research Council categories through differential item function analyses; and (iii) to examine whether the widely used Medical Research Council 12 muscles sum score in patients with Guillain–Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy would meet Rasch models expectations. A total of 1065 patients were included from nine cohorts with the following diseases: Guillain–Barré syndrome (n = 480); myotonic dystrophy type-1 (n = 169); chronic inflammatory demyelinating polyradiculoneuropathy (n = 139); limb-girdle muscular dystrophy (n = 105); multifocal motor neuropathy (n = 102); Pompes disease (n = 62) and monoclonal gammopathy of undetermined related polyneuropathy (n = 8). Medical Research Council data of 72 muscles were collected. Rasch analyses were performed on Medical Research Council data for each cohort separately and after pooling data at the muscle level to increase category frequencies, and on the Medical Research Council sum score in patients with Guillain–Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Disordered thresholds were demonstrated in 74–79% of the muscles examined, indicating physicians’ inability to discriminate between most Medical Research Council categories. Factors such as physicians’ experience or illness type did not influence these findings. Thresholds were restored after rescoring the Medical Research Council grades from six to four options (0, paralysis; 1, severe weakness; 2, slight weakness; 3, normal strength). The Medical Research Council sum score acceptably fulfilled Rasch model expectations after rescoring the response options and creating subsets to resolve local dependency and item bias on diagnosis. In conclusion, a modified, Rasch-built four response category Medical Research Council grading system is proposed, resolving clinicians’ inability to differentiate among its original response categories and improving clinical applicability. A modified Medical Research Council sum score at the interval level is presented and is recommended for future studies in Guillain–Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa

Clinical trials have demonstrated beneficial effects of enzyme replacement therapy (ERT) with alglucosidase alfa in infants, children and adults with Pompe disease. Recent studies have shown that high antibody titers can occur in patients receiving ERT and counteract the effect of treatment. This particularly occurs in those patients with classic-infantile Pompe disease that do not produce any endogenous acid α-glucosidase (CRIM-negative). It is still unclear to what extent antibody formation affects the outcome of ERT in adults with residual enzyme activity. We present the case of a patient with adult-onset Pompe disease. He was diagnosed at the age of 39years by enzymatic testing (10.7% residual activity in fibroblasts) and DNA analysis (genotype: c.-32-13T>G/p.Trp516X). Infusion-associated reactions occurred during ERT and the patients disease progressed. Concurrently, the antibody titer rose to a similarly high level as reported for some CRIM-negative patients with classic-infantile Pompe disease. Using newly developed immunologic-assays we could calculate that approximately 40% of the administered alglucosidase alfa was captured by circulating antibodies. Further, we could demonstrate that uptake of alglucosidase alfa by cultured fibroblasts was inhibited by admixture of the patients serum. This case demonstrates that also patients with an appreciable amount of properly folded and catalytically active endogenous acid α-glucosidase can develop antibodies against alglucosidase alfa that affect the response to ERT.

Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

BackgroundDue partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression.MethodsWe conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA.ResultsBetween October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of −1.3% point/year for manual muscle testing and of −2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast.ConclusionsRecognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.

Effect of enzyme therapy and prognostic factors in 69 adults with Pompe disease: an open-label single-center study

BackgroundEnzyme replacement therapy (ERT) in adults with Pompe disease, a progressive neuromuscular disorder, is of promising but variable efficacy. We investigated whether it alters the course of disease, and also identified potential prognostic factors.MethodsPatients in this open-label single-center study were treated biweekly with 20 mg/kg alglucosidase alfa. Muscle strength, muscle function, and pulmonary function were assessed every 3–6 months and analyzed using repeated-measures ANOVA.ResultsSixty-nine patients (median age 52.1 years) were followed for a median of 23 months. Muscle strength increased after start of ERT (manual muscle testing 1.4 percentage points per year (pp/y); hand-held dynamometry 4.0 pp/y; both p < 0.001). Forced vital capacity (FVC) remained stable when measured in upright, but declined in supine position (−1.1 pp/y; p = 0.03). Muscle function did not improve in all patients (quick motor function test 0.7 pp/y; p = 0.14), but increased significantly in wheelchair-independent patients and those with mild and moderate muscle weakness.Relative to the pre-treatment period (49 patients with 14 months pre-ERT and 22 months ERT median follow-up), ERT affected muscle strength positively (manual muscle testing +3.3 pp/y, p < 0.001 and hand-held dynamometry +7.9 pp/y, p < 0.001). Its effect on upright FVC was +1.8 pp/y (p = 0.08) and on supine FVC +0.8 (p = 0.38). Favorable prognostic factors were female gender for muscle strength, and younger age and better clinical status for supine FVC.ConclusionsWe conclude that ERT positively alters the natural course of Pompe disease in adult patients; muscle strength increased and upright FVC stabilized. Functional outcome is probably best when ERT intervention is timely.

Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants

Pompe disease is an autosomal recessive lysosomal glycogen storage disorder, characterized by progressive muscle weakness. Deficiency of acid α‐glucosidase (EC; 3.2.1.20/3) can be caused by numerous pathogenic variants in the GAA gene. The Pompe Disease Mutation Database at http://www.pompecenter.nl aims to list all variants and their effect. This update reports on 94 variants. We examined 35 novel and 34 known mutations by site‐directed mutagenesis and transient expression in COS‐7 cells or HEK293T cells. Each of these mutations was given a severity rating using a previously published system, based on the level of acid α‐glucosidase activity in medium and transfected cells and on the quantity and quality of the different molecular mass species in the posttranslational modification and transport of acid α‐glucosidase. This approach enabled to classify 55 missense mutations as pathogenic and 13 as likely nonpathogenic. Based on their nature and the use of in silico analysis (Alamut® software), 12 of the additional 25 novel mutations were predicted to be pathogenic including 4 splicing mutations, 6 mutations leading to frameshift, and 2 point mutations causing stop codons. Seven of the additional mutations were considered nonpathogenic (4 silent and 3 occurring in intron regions), and 6 are still under investigation. Hum Mutat 33:1161–1165, 2012.

The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients

Pompe disease is a lysosomal storage disorder characterized by progressive muscle weakness. With the emergence of new treatment options, psychometrically robust outcome measures are needed to monitor patients’ clinical status. We constructed a motor function test that is easy and quick to use. The Quick Motor Function Test (QMFT) was constructed on the basis of the clinical expertise of several physicians involved in the care of Pompe patients; the Gross Motor Function Measure and the IPA/Erasmus MC Pompe survey. The test comprises 16 items. Validity and test reliability were determined in a cohort of 91 Pompe patients (5 to 76 years of age). In addition, responsiveness of the scale to changes in clinical condition over time was examined in a subgroup of 18 patients receiving treatment and 23 untreated patients. Interrater and intrarater reliabilities were good (intraclass correlation coefficients: 0.78 to 0.98 and 0.76 to 0.98). The test correlated strongly with proximal muscle strength assessed by hand held dynamometry and manual muscle testing (rs= 0.81, rs=0.89), and showed significant differences between patient groups with different disease severities. A clinical-empirical exploration to assess responsiveness showed promising results, albeit it should be repeated in a larger group of patients. In conclusion, the Quick Motor Function Test can reliably rate clinical severity and motor function in children and adults with Pompe disease.

PAS-positive lymphocyte vacuoles can be used as diagnostic screening test for Pompe disease.

Screening of blood films for the presence of periodic acid-Schiff (PAS)-positive lymphocyte vacuoles is sometimes used to support the diagnosis of Pompe disease, but the actual diagnostic value is still unknown. We collected peripheral blood films from 65 untreated Pompe patients and 51 controls. Lymphocyte vacuolization was quantified using three methods: percentage vacuolated lymphocytes, percentage PAS-positive lymphocytes, and a PAS score depending on staining intensity. Diagnostic accuracy of the tests was assessed using receiver operating characteristic (ROC) curves. All three methods fully discerned classic infantile patients from controls. The mean values of patients with milder forms of Pompe disease were significantly higher than those of controls, but full separation was not obtained. The area under the ROC curve was 0.98 for the percentage vacuolated lymphocytes (optimal cutoff value 3; sensitivity 91%, specificity 96%) and 0.99 for the percentage PAS-positive lymphocytes and PAS score (optimal cutoff value 9; sensitivity 100%, specificity 98%). Our data indicate that PAS-stained blood films can be used as a reliable screening tool to support a diagnosis of Pompe disease. The percentage of PAS-positive lymphocytes is convenient for use in clinical practice but should always be interpreted in combination with other clinical and laboratory parameters.

Long-term benefit of enzyme replacement therapy in Pompe disease: A 5-year prospective study

Objective: To determine the effect of enzyme replacement therapy (ERT) after 5 years and to identify predictors for a favorable response because few data are available on the long-term efficacy of ERT in Pompe disease. Methods: We included 102 adult patients with Pompe disease in a nationwide, prospective cohort study. We assessed muscle strength (manual muscle testing with Medical Research Council [MRC] grading, handheld dynamometry [HHD]), muscle function (6-minute walk test, Quick Motor Function Test), daily life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale), and pulmonary function (forced vital capacity [FVC] in upright and supine positions, maximum inspiratory and expiratory pressures) at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements. Results: Median follow-up duration was 6.1 years (range 0.4–7.9 years), of which 5.0 years (range 0.2–7.3 years) were during ERT. Treated patients had better muscle strength (MRC sum score +6.6 percentage points [pp]; HHD sum score +9.6 pp, both p < 0.0001), activity levels (R-PAct +10.8 pp, p < 0.002), and pulmonary function (FVC upright +7.3 pp, FVC supine +7.6 pp, both p < 0.0003) than expected for their untreated disease course. Walking distance improved (416 vs 376 m at baseline, p = 0.03). The largest increase was seen during the first 2 to 3 years of treatment. Response to treatment was similar between groups regardless of sex, age, or disease duration. Conclusions: Long-term ERT positively affects muscle strength, pulmonary function, and daily life activities in adult patients with Pompe disease, with a peak effect at ≈2 to 3 years of treatment. Classification of evidence: This study provides Class IV evidence that for patients with Pompe disease, long-term ERT positively affects muscle strength, pulmonary function, and daily life activities.

Hearing in adults with Pompe disease

Hearing loss has been recognized as an important cause of morbidity in infants with Pompe disease, a metabolic disorder caused by deficiency of acid α-glucosidase. It is unknown whether hearing is also affected in adult Pompe patients. We have studied the prevalence, severity, and type of hearing loss in 58 adult patients using tympanometry and pure-tone audiometry. Compared to normative data (International Organisation for Standardisation standard 7029), 72% of patients had impaired hearing thresholds at one or more frequencies in at least one ear. All measured frequencies were equally affected. All patients had a sensorineural type of hearing loss, pointing to cochlear or retrocochlear pathology. Categorised according to the standards of the World Health Organisation 21% of patients had a clinically relevant hearing loss (16% slight, 3% moderate, 2% profound). Though this suggests that hearing loss occurs in a considerable number of patients with Pompe disease, this prevalence is similar to that in the general population. Therefore, we conclude that hearing loss is not a specific feature of Pompe disease in adults.

Pompe disease in adulthood: effects of antibody formation on enzyme replacement therapy.

Purpose:To determine the effect of antibodies against recombinant human acid α-glucosidase (rhGAA) on treatment efficacy and safety, and to test whether the GAA genotype is involved in antibody formation.Methods:We used enzyme-linked immunosorbent assay (ELISA) to determine anti-rhGAA antibody titers at baseline and at 6, 12, and 36 months of rhGAA treatment. We measured the capacity of antibodies to neutralize rhGAA enzymatic activity or cellular uptake and the effects on infusion-associated reactions (IARs), muscle strength, and pulmonary function.Results:Of 73 patients, 45 developed antibodies. Maximal titers were high (≥1:31,250) in 22% of patients, intermediate (1:1,250–1:31,250) in 40%, and none or low (0–1:1,250) in 38%. The common IVS1/delex18 GAA genotype was absent only in the high-titer group. The height of the titer positively correlated with the occurrence and number of IARs (P ≤ 0.001). On the group level, antibody titers did not correlate with treatment efficacy. Eight patients (11%) developed very high maximal titers (≥156,250), but only one patient showed high sustained neutralizing antibodies that probably interfered with treatment efficacy.Conclusions:In adults with Pompe disease, antibody formation does not interfere with rhGAA efficacy in the majority of patients, is associated with IARs, and may be attenuated by the IVS1/delex18 GAA genotype.Genet Med 19 1, 90–97.