Volume 33, Issue 4

The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene ( HTT ) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis - (DNA repair genes) and trans - (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.

The cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset and recessively inherited ataxia. For many years, CANVAS has been diagnosed based on the clinical phenotype. Only recently, a large biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 ( RFC1 ) gene has been identified as the underlying genetic cause for the large majority of CANVAS cases. Subsequently, other phenotypes such as ataxia with chronic cough, incomplete CANVAS and MSA-C-like phenotypes have been associated with biallelic RFC1 repeat expansions. Because of this heterogeneity it has been suggested to change the name of the disease to “RFC1 disease”. Chronic cough is characteristic and can precede neurological symptoms by years or decades. In the neurological examination signs of cerebellar, sensory, and vestibular ataxia are frequently observed. Nerve conduction studies usually show absent or markedly reduced sensory nerve action potentials. On brain MRI cerebellar degeneration and spinal cord alterations are common. In later disease stages more widespread neurodegeneration with additional involvement of the brainstem and basal ganglia is possible. As yet, the exact incidence of RFC1 -associated neurological diseases remains uncertain although first studies suggest that RFC1 -related ataxia is common. Moreover, the pathophysiological mechanisms caused by the large biallelic pentanucleotide repeat expansions in RFC1 remain elusive. Future molecular and genetic research as well as natural history studies are highly desirable to pave the way towards personalized treatment approaches.

Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by myoclonus and seizures. The genetic variant underlying FAME is an intronic repeat expansion composed of two different pentamers: an expanded TTTTA, which is the motif originally present at the locus, and an insertion of TTTCA repeats, which is usually located at the 3′ end and likely corresponds to the pathogenic part of the expansion. This repeat expansion has been identified so far in six genes located on different chromosomes, which remarkably encode proteins with distinct cellular localizations and functions. Although the exact pathophysiological mechanisms remain to be clarified, it is likely that FAME repeat expansions lead to disease independently of the gene where they occur. We herein review the clinical and molecular characteristics of this singular genetic disorder, which interestingly shares clinical features with other more common neurological disorders whose etiology remains mainly unsolved.

X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative movement disorder, caused by a founder retrotransposon insertion in an intron of the TAF1 gene. This insertion contains a polymorphic hexanucleotide repeat (CCCTCT) n , the length of which inversely correlates with the age at disease onset (AAO) and other clinical parameters, aligning XDP with repeat expansion disorders. Nevertheless, many other pathogenic mechanisms are conceivably at play in XDP, indicating that in contrast to other repeat disorders, the (CCCTCT) n repeat may not be the actual (or only) disease cause. Here, we summarize and discuss genetic and molecular aspects of XDP, highlighting the role of the hexanucleotide repeat in age-related disease penetrance and expressivity.

Noncoding repeat expansions are a well-known cause of genetic disorders mainly affecting the central nervous system. Missed by most standard technologies used in routine diagnosis, pathogenic noncoding repeat expansions have to be searched for using specific techniques such as repeat-primed PCR or specific bioinformatics tools applied to genome data, such as ExpansionHunter. In this review, we focus on GC-rich repeat expansions, which represent at least one third of all noncoding repeat expansions described so far. GC-rich expansions are mainly located in regulatory regions (promoter, 5′ untranslated region, first intron) of genes and can lead to either a toxic gain-of-function mediated by RNA toxicity and/or repeat-associated non-AUG (RAN) translation, or a loss-of-function of the associated gene, depending on their size and their methylation status. We herein review the clinical and molecular characteristics of disorders associated with these difficult-to-detect expansions.

Objectives The aim of this survey was to investigate the career satisfaction of human genetics residents in Germany and to analyse the influence of intrinsic and extrinsic factors. Methods We developed an online survey for the evaluation of a broad range of factors concerning the situation of human genetics residents in Germany using validated questionnaires and adding human genetics specific items to them. Human genetics residents working at institutions with an authorization for specialist training were asked to participate in the online survey. To analyse the situation of specialist training in human genetics and the influence of multiple factors on career satisfaction, descriptive statistics, mean descriptive statistics and comparisons of mean values as well as multiple linear regression analyses were carried out. Results Of the 71 institutions contacted, 41 (58 %) provided feedback and reported the number of 114 residents in human genetics. In total, 58 residents completed the questionnaire (50.9 %). Overall career satisfaction was high with a mean score of 30.8 (scale ranging from 8–40). Factors significantly influencing career satisfaction were general life satisfaction, occupational self-efficacy expectations and content with the doctors entitled to the specialty training. Except for the reduced perception to achieve their professional goals expressed by women with children, career satisfaction was influenced by neither gender nor parental status, other sociodemographic factors, variables concerning the personal professional life and the residency in general, the subjective perceived workload nor the site of specialist training. Participation in research activities differed significantly between male and female residents. The residents’ assessment of their own professional prospects and the prospects of the subject were consistently positive, even though residents consider the current requirement planning by the GB-A for human geneticists as inappropriate and believe that human genetics is not yet firmly anchored as a specialist discipline in the consciousness of other medical colleagues and the general public. Conclusions Career satisfaction of German human genetics residents is generally high and mainly influenced by life satisfaction, occupational self-efficacy expectations and quality of the specialist training. In contrast to other specialties career satisfaction seems to be independent from gender or parental status even though male residents were significantly more often involved in research activities. In order to keep human genetics residents in the specialty, measures that enable balanced professional and care work as well as continuous improvement of specialist education, e. g. through the implementation of structured curricula and continuing education of the doctors entitled to specialist training, is of great importance.