Anneke J.A. Kievit

DNAJC6 Mutations Associated with Early-Onset Parkinson's Disease

DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair‐bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early‐onset Parkinsons disease (PD).

Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.

Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency

ECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh‐like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations.

Mutations in TMEM230 are not a common cause of Parkinson's disease

and 207 sporadic PD (SPD) patients. The study also included 200 ET patients consisting of 100 familial ET patients and 100 sporadic ET patients. In addition, 400 healthy subjects served as controls (Table 1). We received approval from the Ethics Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. Written informed consent from all participants was obtained. Genomic DNA amplification and Sanger sequencing were done to detect the stop codon. DNASTAR Lasergene MegAlign (v7.1.0) and Chromas (v2.33) were used to conduct sequence alignment. We failed to find any variants in the TAG stop codon in all patients and controls. However, our study had some limitations. First, the sample of our study may be not big enough to detect rare mutations, but it should be noted that the frequency of the mutation in Chinese PD patients was 3.1% in Deng’s study. In that case, we should have identified a few carriers. Second, most of our patients were from eastern China, especially Shanghai, which might be regionally different from the participants in Deng’s study, about which we have no information. Third, although we failed to identify mutations in the TAG codon, we did not assess the whole coding region of TMEM230 either; thus, other mutations in this gene may be present. In conclusion, the stop codon mutation is rare in PD and ET patients from China, especially eastern China, based on our study. Still, additional studies are needed to verify the role of TMEM230 mutations in PD or other neurological diseases.

Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects

To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias, and spastic paraplegia.

How Do I Assess a Family Tree for Inheritance Patterns?: family tree assessment

An accurate collection and evaluation of the family history remains an important part in the clinical evaluation of every patient. Knowledge of a patients family history is useful for diagnosis and risk assessment of relatively uncommon single‐gene disorders, such as fragile X syndrome, Huntingtons disease, and other disorders, inherited following the classical Mendelian patterns. Moreover, a positive family history is a major risk factor for several common diseases, including neurodegenerative disease and movement disorders. Here, we first show how to draw a pedigree, and we then use patient cases to practice in the recognition of the inheritance patterns.

Hemophilia B in a female with intellectual disability caused by a deletion of Xq26.3q28 encompassing the F9

Hemophilia B is an X‐linked recessive disorder caused by mutations in the F9 on Xq27.1. Mainly males are affected but about 20% of female carriers have clotting factor IX activity below 0.40 IU/ml and bleeding problems. Fragile‐X syndrome (FMR1) and FRAXE syndrome (AFF2) are well‐known causes of X‐linked recessive intellectual disability. Simultaneous deletion of both FMR1 and AFF2 in males results in severe intellectual disability. In females the phenotype is more variable. We report a 19‐year‐old female with severe intellectual disability and a long‐standing bleeding history.