Jan B. M. Kuks

Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene

BACKGROUND Desmin-related myopathy is a clinically heterogenous group of disorders encompassing myopathies, cardiomyopathies, conduction disease, and combinations of these disorders. Mutations in the gene encoding desmin (DES), a major intermediate filament protein, can underlie this phenotype. OBJECTIVE The purpose of this study was to investigate the clinical and pathologic characteristics of 27 patients from five families with an identical mutation in the head domain region (p.S13F) of desmin. METHODS/RESULTS All 27 carriers or obligate carriers of a p.S13F DES founder mutation demonstrated a fully penetrant yet variable phenotype. All patients demonstrated cardiac involvement characterized by high-grade AV block at young ages and important right ventricular (RV) involvement. RV predominance was demonstrated by the presence of right bundle branch block in 10 patients (sometimes as a first manifestation) and by RV heart failure in 6 patients, including 2 patients who fulfilled the diagnostic criteria for arrhythmogenic RV cardiomyopathy. Because of this clinical overlap with desmosome cardiomyopathies, we also studied the organization of the intercalated disks, particularly the distribution of desmosomal proteins. Normal amounts of the major desmosomal proteins were found, but the intercalated disks were more convoluted and elongated and had a zigzag appearance. CONCLUSION In this largest series to date of individuals with a single head domain DES mutation, patients show a variable yet predominantly cardiologic phenotype characterized by conduction disease at an early age and RV involvement including right bundle branch block and/or RV tachycardias and arrhythmogenic RV cardiomyopathy phenocopies. A localized effect of desmin on the structure of the cardiac intercalated disks might contribute to disease pathogenesis.

Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy

Reply from the Authors: We thank Dr. Nabbout et al. for their comments on our article, in which we described 13 probands, and one of their mothers, with epilepsy variably associated with mental retardation and autistic features in whom the PCDH19 gene was mutated.1 The epilepsy phenotype was variable. Seven patients exhibited DS and 6 had focal epilepsy. These figures confirm that PCDH19 mutations can cause an epileptic encephalopathy resembling DS in girls.2 Therefore, if screening for SCN1A gene mutations, deletions, amplification, or duplications yields negative results, PCDH19 should be screened. In our cohort, girls with PCDH19 mutations and focal epilepsy had early seizure onset and either normal cognitive skills or mental retardation and autistic features. The spectrum of phenotypes associated with PCDH19 mutations is broad, ranging from mild epilepsy to a severe epileptic encephalopathy. Such phenotypic diversity might be partially explained by the cosegregation of other genetic factors either rescuing or worsening the phenotype. Since our article was accepted for publication, we have observed 6 more girls with PCDH19 mutations, none having a phenotype evocative of DS (unpublished data). Another article reported 3 girls with seizure onset in infancy and varying degrees of cognitive impairment and autistic features.3 However, the core clinical features of PCDH19-related epilepsy phenotypes seem to be early onset of seizures occurring in clusters and precipitated by fever. The spectrum of associated cognitive and behavioral impairment is variable and its relationship with epilepsy severity is not obvious. PCDH19 is clearly emerging as a major epilepsy gene in females. Analysis of larger cohorts, with unbiased recruitment, will clarify the full range of phenotypes caused by alterations in this gene.

Strong association of MuSK antibody–positive myasthenia gravis and HLA-DR14-DQ5

The authors studied the HLA profile of 23 white Dutch patients with muscle-specific kinase antibody–positive myasthenia gravis (MuSK Ab+ MG) and found an association with HLA-DR14-DQ5 (odds ratio 8.5; 95% CI 3.9 to 18.7; p = 4.9 × 10−5). Fifty-two percent of the patients carried the DR14 allele compared with 5% of the controls (p = 1.0 × 10−8). This association between MuSK Ab+ MG and a relatively rare HLA haplotype differs from the previously described association of early-onset acetylcholine receptor Ab+ MG with HLA-B8-DR3.

Difference in distribution of muscle weakness between myasthenia gravis and the Lambert–Eaton myasthenic syndrome

Background: Myasthenia gravis and the Lambert–Eaton myasthenic syndrome (LEMS) may have a similar distribution of muscle weakness. Deciding on a diagnosis of myasthenia gravis or LEMS on clinical grounds may therefore be difficult. Objective: To compare the localisation of initial muscle weakness and the distribution of weakness at the time of maximum severity in patients with myasthenia gravis and LEMS. Subjects: 101 patients with myasthenia gravis and 38 patients with LEMS. Results: In myasthenia gravis, initial weakness involved extraocular muscles in 59%, bulbar muscles in 29%, and limb muscles in 12% of the patients. In LEMS no patient had ocular weakness, 5% had bulbar weakness, and 95% had weakness of the limbs as the first symptom (p < 0.001). At the point of maximum severity, weakness in myasthenia gravis was purely ocular in 25%, oculobulbar in 5%, restricted to the limbs in 2%, and present in both oculobulbar muscles and limbs in 68%. At this point, none of the LEMS patients had weakness restricted to extraocular or bulbar muscles (p = 0.002). The legs were affected in all LEMS patients, whereas in 12 patients with generalised myasthenia gravis limb weakness was restricted to the arms (p = 0.024). Conclusions: In a patient suspected to have a myasthenic syndrome whose first symptom is ocular weakness, LEMS is virtually excluded. Limb weakness confined to the arms is only found in generalised myasthenia gravis and not in LEMS. Muscle weakness in myasthenia gravis tends to develop in a craniocaudal direction, and in the opposite direction in LEMS.

The Lambert–Eaton myasthenic syndrome 1988–2008: A clinical picture in 97 patients

BACKGROUND Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC. PATIENTS AND METHODS In our study we included 52 LEMS patients with SCLC and 45 non-tumor patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS. RESULTS In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles (p=0.0001), distal arm muscles (p=0.0037), distal leg muscles (p=0.0002), dysartria (p=0.0091) and the presence of erectile dysfunction (p=0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS. CONCLUSION A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC-LEMS and NT-LEMS.

Clinical Dutch-English Lambert-Eaton Myasthenic Syndrome (LEMS) Tumor Association Prediction Score Accurately Predicts Small-Cell Lung Cancer in the LEMS

PURPOSE Approximately one half of patients with Lambert-Eaton myasthenic syndrome (LEMS) have small-cell lung carcinomas (SCLC), aggressive tumors with poor prognosis. In view of its profound impact on therapy and survival, we developed and validated a score to identify the presence of SCLC early in the course of LEMS. PATIENTS AND METHODS We derived a prediction score for SCLC in LEMS in a nationwide cohort of 107 Dutch patients, and validated it in a similar cohort of 112 British patients. A Dutch-English LEMS Tumor Association Prediction (DELTA-P) score was developed based on multivariate logistic regression. RESULTS Age at onset, smoking behavior, weight loss, Karnofsky performance status, bulbar involvement, male sexual impotence, and the presence of Sry-like high-mobility group box protein 1 serum antibodies were independent predictors for SCLC in LEMS. A DELTA-P score was derived allocating 1 point for the presence of each of the following items at or within 3 months from onset: age at onset ≥ 50 years, smoking at diagnosis, weight loss ≥ 5%, bulbar involvement, erectile dysfunction, and Karnofsky performance status lower than 70. The area under the curve of the receiver operating curve was 94.4% in the derivation cohort and 94.6% in the validation set. A DELTA-P score of 0 or 1 corresponded to a 0% to 2.6% chance of SCLC, whereas scores of 4, 5, and 6 corresponded to chances of SCLC of 93.5%, 96.6%, and 100%, respectively. CONCLUSION The simple clinical DELTA-P score discriminated patients with LEMS with and without SCLC with high accuracy early in the course of LEMS.

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.

Motivation for body donation to science: More than an altruistic act

BACKGROUND In recent years the Netherlands has witnessed a steep increase in the number of bodies donated for medical research and training. To explore this upward trend and motives for donation, a survey was conducted among registered body donors in the database of the Department of Anatomy at the University Medical Center of Groningen (UMCG). METHODS In November 2008, postal questionnaires were sent to 996 people enrolled at the UMCG body donor database. The present study focuses on motives for donation and social background characteristics of the body donors. FINDINGS Registered donors responded quickly and the survey response rate was high (76%). The mean age of respondents was 69 years and the majority described themselves as Dutch (98%) and non-church affiliated (79%). One quarter (25%) of the respondents are/were health care professionals and 11% involved in education. Principal factor analysis revealed three dimensions underlying ten different motivations for body donation: a desire to be useful after death, a negative attitude towards funerals and expression of gratitude. Despite the current economic recession only 8% of respondents are prompted by money motives to bequeath their bodies. CONCLUSIONS The majority of motives for body donation stem from the wish to be useful after death. However, the present survey suggests that body donation is more than an altruistic act; people are also motivated by personal benefit. Results of our survey contradict the notion that body donation stems from loneliness. Many donors have a supportive social network and meaningful social relationships. People moreover propagate body donation within their social networks.

Epidemiology of myasthenia gravis with anti‐muscle specific kinase antibodies in the Netherlands

The epidemiology of myasthenia gravis subtypes and the frequency of antibodies to muscle-specific kinase (MuSK) was studied in patients with generalised myasthenia gravis without anti-acetylcholine receptor antibodies who had an onset of symptoms between 1990 and 2004 in a well-defined region in the Netherlands. The nationwide prevalence and incidence of myasthenia gravis with anti-MuSK antibodies were also studied. MuSK antibodies were found in 22% of patients with generalised myasthenia gravis without anti-acetylcholine receptor antibodies. Nationwide, 35 patients with MuSK myasthenia gravis were identified, yielding a prevalence of 1.9 per million (95% confidence interval (CI) 1.22 to 2.59) and an annual incidence 0.10 per million person-years (95% CI 0.06 to 0.14).