Bart P. van de Warrenburg

Neurological gait disorders in elderly people: clinical approach and classification

Gait disorders are common and often devastating companions of ageing, leading to reductions in quality of life and increased mortality. Here, we present a clinically oriented approach to neurological gait disorders in the elderly population. We also draw attention to several exciting scientific developments in this specialty. Our first focus is on the complex and typically multifactorial pathophysiology underlying geriatric gait disorders. An important new insight is the recognition of gait as a complex higher order form of motor behaviour, with prominent and varied effects of mental processes. Another relevant message is that gait disorders are not an unpreventable consequence of ageing, but implicate the presence of underlying diseases that warrant specific diagnostic tests. We next discuss the core clinical features of common geriatric gait disorders and review some bedside tests to assess gait and balance. We conclude by proposing a practical three-step approach to categorise gait disorders and we present a simplified classification system based on clinical signs and symptoms.

A Post-Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene‐specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger‐based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite‐stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.

How might physical activity benefit patients with Parkinson disease

Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive motor and nonmotor impairments. These impairments incline many patients towards a sedentary lifestyle, which has many deleterious consequences. Accumulating evidence suggests that patients with PD might benefit from physical activity and exercise in a number of ways, from general improvements in health to disease-specific effects and, potentially, disease-modifying effects (suggested by animal data). Many issues remain to be addressed, including the need to perform clinical trials to demonstrate these presumed benefits of physical activity and exercise in patients with PD. These trials must also address safety issues, such as an increased risk of falls and cardiovascular complications in more-active patients. Identifying ways to induce a sustained behavioral change, using specifically tailored programs that address potential barriers such as depression, apathy and postural instability, may lead to an improved quality of life in individuals with PD.

Genome-wide association study confirms extant PD risk loci among the Dutch.

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinsons disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P=1.63 × 10−5, OR=1.325 and BST1, rs12502586: P=1.63 × 10−3, OR=1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3′ and 5′ ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P=1.22 × 10−4, OR=1.51; HLA, rs4248166: P=4.39 × 10−5, OR=1.36; and MAPT, rs3785880: P=1.9 × 10−3, OR=1.19).

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis

Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.

Reliability and Validity of the international cooperative ataxia rating scale: A study in 156 spinocerebellar ataxia patients

To evaluate the efficacy of treatments in spinocerebellar ataxias (SCAs), appropriate clinical scales are required. This study evaluated metric properties of the International Cooperative Ataxia Rating Scale (ICARS) in 156 SCA patients and 8 controls. ICARS was found to be a reliable scale satisfying accepted criteria for interrater reliability, test–retest reliability, and internal consistency. Although validity testing was limited, we found evidence of validity of ICARS when ataxia disease stages and Barthel index were used as external criteria. On the other hand, our study revealed two major problems associated with the use of ICARS. First, the redundant and overlapping nature of several items gave rise to a considerable number of contradictory ratings. Second, a factorial analysis showed that the rating results were determined by four different factors that did not coincide with the ICARS subscales, thus questioning the justification of ICARS subscore analysis in clinical trials.

Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6.

BACKGROUND AND OBJECTIVE Biomarkers to monitor neurological dysfunction in autosomal dominant inherited spinocerebellar ataxias (SCA) are lacking. We therefore aimed to visualize, quantify and correlate localized brain atrophy with clinical symptoms in SCA1, SCA3, and SCA6. METHODS We compared patients suffering from SCA1 (n=48), SCA3 (n=24), and SCA6 (n=10) with 32 controls using magnetic resonance imaging (MRI) on four different scanners in eight centers followed by voxel-based morphometry (VBM) and quantitative three-dimensional (3D) volumetry. RESULTS SCA1 and SCA3 patients presented with severe atrophy in total brainstem (consisting of midbrain, pons, and medulla), pons, medulla, total cerebellum, cerebellar hemispheres and cerebellar vermis, putamen and caudate nucleus. Atrophy in the cerebellar hemispheres was less severe in SCA3 than in SCA1 and SCA6. Atrophy in SCA6 was restricted to the grey matter of the cerebellum (VBM and volumetry), total brainstem and pons (volumetry only). Overall, we did not observe substantial atrophy in the cerebral cortex. A discriminant analysis taking into account data from pons, cerebellar hemispheres, medulla, midbrain and putamen achieved a reclassification probability of 81.7% for SCA1, SCA3, and SCA6. The repeat length of the expanded allele showed a weak negative correlation with the volume of the brainstem, pons, caudate nucleus and putamen in SCA3, and a weak correlation with the pons in SCA1, whereas no such correlation was found in SCA6. Clinical dysfunction as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the Unified Huntingtons Disease Rating Scale functional assessment correlated best with the atrophy of pons in SCA1, with total brainstem atrophy in SCA3 and atrophy of total cerebellum in SCA6. CONCLUSIONS Our data provide strong evidence that MRI is an attractive surrogate marker for clinical studies of SCA. In each SCA genotype clinical dysfunction may be caused by different patho-anatomical processes.

Movement disorders in spinocerebellar ataxias

Autosomal dominant spinocerebellar ataxias (SCAs) can present with a large variety of noncerebellar symptoms, including movement disorders. In fact, movement disorders are frequent in many of the various SCA subtypes, and they can be the presenting, dominant, or even isolated disease feature. When combined with cerebellar ataxia, the occurrence of a specific movement disorder can provide a clue toward the underlying genotype. There are reasons to believe that for some coexisting movement disorders, the cerebellar pathology itself is the culprit, for example, in the case of cortical myoclonus and perhaps dystonia. However, movement disorders in SCAs are more likely related to extracerebellar pathology, and imaging and neuropathological data indeed show involvement of other parts of the motor system (substantia nigra, striatum, pallidum, motor cortex) in some SCA subtypes. When confronted with a patient with an isolated movement disorder, that is, without ataxia, there is currently no reason to routinely screen for SCA gene mutations, the only exceptions being SCA2 in autosomal dominant parkinsonism (particularly in Asian patients) and SCA17 in the case of a Huntingtons disease–like presentation without an HTT mutation.

Prodynorphin Mutations Cause the Neurodegenerative Disorder Spinocerebellar Ataxia Type 23

Spinocerebellar ataxias (SCAs) are dominantly inherited neurodegenerative disorders characterized by progressive cerebellar ataxia and dysarthria. We have identified missense mutations in prodynorphin (PDYN) that cause SCA23 in four Dutch families displaying progressive gait and limb ataxia. PDYN is the precursor protein for the opioid neuropeptides, α-neoendorphin, and dynorphins A and B (Dyn A and B). Dynorphins regulate pain processing and modulate the rewarding effects of addictive substances. Three mutations were located in Dyn A, a peptide with both opioid activities and nonopioid neurodegenerative actions. Two of these mutations resulted in excessive generation of Dyn A in a cellular model system. In addition, two of the mutant Dyn A peptides induced toxicity above that of wild-type Dyn A in cultured striatal neurons. The fourth mutation was located in the nonopioid PDYN domain and was associated with altered expression of components of the opioid and glutamate system, as evident from analysis of SCA23 autopsy tissue. Thus, alterations in Dyn A activities and/or impairment of secretory pathways by mutant PDYN may lead to glutamate neurotoxicity, which underlies Purkinje cell degeneration and ataxia. PDYN mutations are identified in a small subset of ataxia families, indicating that SCA23 is an infrequent SCA type (∼0.5%) in the Netherlands and suggesting further genetic SCA heterogeneity.

Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia.