G.W.A.M. Padberg

Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN-I

Objective: To assess the prevalence of severe fatigue and its relation to functional impairment in daily life in patients with relatively common types of neuromuscular disorders. Methods: 598 patients with a neuromuscular disease were studied (139 with facioscapulohumeral dystrophy, 322 with adult onset myotonic dystrophy, and 137 with hereditary motor and sensory neuropathy type I). Fatigue severity was assessed with Checklist Individual Strength (CIS-fatigue). Functional impairments in daily life were measured with the short form 36 item health questionnaire (SF-36). Results: The three different neuromuscular patient groups were of similar age and sex. Severe experienced fatigue was reported by 61–74% of the patients. Severely fatigued patients had more problems with physical functioning, social functioning, mental health, bodily pain, and general health perception. There were some differences between the three disorders in the effects of fatigue. Conclusions: Severe fatigue is reported by the majority of patients with relatively common types of neuromuscular disorders. Because experienced fatigue severity is associated with the severity of various functional impairments in daily life, it is a clinically and socially relevant problem in this group of patients.

Linkage of Autosomal Dominant Hearing Loss to the Short Arm of Chromosome 1 in Two Families

BACKGROUND At least half of the cases of profound deafness of early onset are caused by genetic factors, but few of the genetic defects have been identified. This is particularly true of the most common hereditary forms of deafness, which occur in the absence of any associated syndrome. METHODS We studied a large Indonesian family in which hearing loss was inherited in an autosomal dominant pattern. The hearing loss first affects the high frequencies during the teens or 20s and becomes profound within 10 years. To locate the responsible gene, we performed genetic-linkage analysis, using microsatellite markers distributed over the entire genome. We then performed linkage analyses in an American family and a Dutch family with similar patterns of hereditary hearing loss. RESULTS In the extended Indonesian family, a gene linked to deafness mapped to chromosome 1p, with a multipoint lod score of more than 7. In the American family, deafness was linked to the same locus on chromosome 1p, with a multipoint lod score of more than 5. In the Dutch family, however, this locus was ruled out. The flanking markers D1S255 and D1S211 defined a region of 6 cM on chromosome 1p that is likely to contain the gene associated with deafness in the first two families. CONCLUSIONS In some families with early-onset autosomal dominant hearing loss, the responsible gene is on chromosome 1p.

Population-based incidence and prevalence of facioscapulohumeral dystrophy

Objective: To determine the incidence and prevalence of facioscapulohumeral muscular dystrophy (FSHD) in the Netherlands. Methods: Using 3-source capture-recapture methodology, we estimated the total yearly number of newly found symptomatic individuals with FSHD, including those not registered in any of the 3 sources. To this end, symptomatic individuals with FSHD were available from 3 large population-based registries in the Netherlands if diagnosed within a 10-year period (January 1, 2001 to December 31, 2010). Multiplication of the incidence and disease duration delivered the prevalence estimate. Results: On average, 52 people are newly diagnosed with FSHD every year. This results in an incidence rate of 0.3/100,000 person-years in the Netherlands. The prevalence rate was 12/100,000, equivalent to 2,000 affected individuals. Conclusions: We present population-based incidence and prevalence estimates regarding symptomatic individuals with FSHD, including an estimation of the number of symptomatic individuals not present in any of the 3 used registries. This study shows that the total number of symptomatic persons with FSHD in the population may well be underestimated and a considerable number of affected individuals remain undiagnosed. This suggests that FSHD is one of the most prevalent neuromuscular disorders.

A Second Gene for Autosomal Dominant Mobius Syndrome Is Localized to Chromosome 10q, in a Dutch Family

Möbius syndrome (MIM 157900) consists of a congenital paresis or paralysis of the VIIth (facial) cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is typically affected, and often, also, the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system, and mental retardation are seen in patients with Möbius syndrome. Most cases are sporadic, but familial recurrence can occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Möbius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21-22, in a large Dutch family with Möbius syndrome consisting essentially of autosomal dominant asymmetric bilateral facial paresis. Here we report linkage analysis in a second large Dutch family with autosomal dominant inherited facial paresis. After exclusion of >90% of the genome, we identified the locus on the long arm of chromosome 10 in this family, demonstrating genetic heterogeneity of this condition. The reduced penetrance suggests that at least some of the sporadic cases might be familial.

Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions

To appreciate the involvement of known or potential susceptibility genes in sporadic breast tumors, we have searched for chromosomal deletions by studying loss of heterozygosity (LOH) at 43 microsatellite (CA)n markers from human chromosomes 10, 11 and 17, in 115 unselected consecutive samples of breast carcinoma with particular emphasis on specific regions. No site of consistent LOH was identified on chromosome 10. Five regions of LOH were contained within bands q22-24 of chromosome 11 for which nearly 50% of the tumors had LOH at at least one marker. This region is thus a major site of deletion in breast cancer and several tumor suppressor genes seem to be involved. One of them may be the ataxia telangiectasia (ATM) gene which is located in one of the affected regions. Five regions of LOH, one of which is within the BRCA1 gene area, were recognized along chromosome 17. LOH at three of these regions were found in highly proliferative tumors. When combined with a previous study of chromosome 13 with emphasis on BRCA2 and Rb1 genes, this work allowed to distinguish a total of 12 regions of LOH, variably affected in breast tumors and correlated with prognostic parameters.

High specificity of myositis specific autoantibodies for myositis compared with other neuromuscular disorders

Myositis specific autoantibodies (MSAs) are proven to be specific for myositis compared with other inflammatory connective tissue diseases. Their specificity compared, however, with other neuromuscular disorders, which are included in the differential diagnosis of patients in whom the diagnosis myositis is under consideration, is unknown. We prospectively screened sera from 107 patients with various neuromuscular disorders for the most common MSAs and compared the results with the findings in a group of 97 myositis patients, published previously. Special attention was paid to patients with facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant muscle disease with marked inflammation in skeletal muscle tissue.Only one patient in the neuromuscular disorders group tested positive for an MSA, compared with 41 in the myositis group, resulting in a specificity of 99%. None of the FSHD patients tested positive. We conclude that the tested MSAs are highly specific for myositis and that they are not merely associated with muscle inflammation.

Mutation analysis in the candidate Möbius syndrome genes PGT and GATA2 on chromosome 3 and EGR2 on chromosome 10

Mobius syndrome (MBS, MIM 157900) is a rare congenital disorder characterised by paralysis of the facial nerve. This paralysis may be complete or partial and unilateral or bilateral. Other cranial nerves are often implicated, most frequently the abducens and hypoglossal nerve. Limb malformations and facial dysmorphism occur frequently. Features seen less often in MBS are structural anomalies of the ear, defective branchial musculature (Poland syndrome, MIM 173800), and mild mental retardation.1 Although Mobius syndrome usually occurs in isolated cases, familial recurrence has been reported. Patterns of inheritance observed in affected families suggest different modes of inheritance for the syndrome, ranging from autosomal recessive to autosomal dominant and X linked. To date, four genetic loci for MBS have been described. In 1977, a reciprocal translocation of 13q12.2-13 was identified, cosegregating with the disease in a three generation MBS family.2 Slee et al 3 reported a MBS patient with a deletion of chromosome 13q12.2 in 1991. Therefore, chromosome 13q12.2-q13 is thought to harbour a gene for MBS (MBS1). We identified two additional loci for MBS, MBS2 at 3q21-q224 and MBS3 at 10q21,1 in two large Dutch families with a mild Mobius phenotype, cosegregating in an autosomal dominant fashion with reduced penetrance. A fourth locus harbouring a gene for MBS on chromosome 1p22 was inferred from two reports. Donahue et al 5 identified a t(1;11)(p22;p13) translocation in a patient with Mobius syndrome. The 1p22 locus was confirmed by a t(1;2)(p22.3;q21.1) translocation in a patient with …

Dysphagia in facioscapulohumeral muscular dystrophy.

Dysphagia is not considered a symptom of facioscapulohumeral muscular dystrophy (FSHD). In this study, the authors found that dysphagia does occur in patients with advanced FSHD showing mild involvement of the jaw and lingual muscles. Dysphagia is seldom life threatening in these patients. The authors conclude that dysphagia should not be considered an exclusion criterion for FSHD.

Decreased striatal dopamine-receptor binding in sporadic ALS: Glutamate hyperactivity?

Article abstract The pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. The striatum receives massive glutamatergic input. Animal studies suggest that glutamate decreases striatal D2-receptor synthesis. In drug-naïve, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole. Our findings support the glutamatergic excitotoxicity hypothesis in sporadic ALS.

An unbiased and efficient computerised tomography method to quantify muscle and adipose tissue volume in neuromuscular patients.

The objective was to evaluate the applicability and reliability of an unbiased stereological computerised tomography (CT) method for estimating total human body (HB), skeletal muscle (SM) and adipose tissue (AT) volumes in groups of neuromuscular patients. In 10 neuromuscular patients HB, SM and AT volumes were estimated using systematic sampling on equidistant CT sections throughout the total body axis using a counting grid with systematically ordered intersection points. Each intersection point hitting HB, SM or AT represented a known volume dependent on intersection point distance and sum of section thickness and gap. Random and systematic intra- and interobserver errors for volume estimates were below 0.035. These errors were negligible to the coefficient of variation of the group mean, being 0.190 for HB, 0.323 for SM and 0.471 for AT. Even in the presence of intrafascicular and intramuscular fat in neuromuscular patients, unbiased and reliable quantification of HB, SM and AT is possible.