The few previously reported patients with familial parkinsonism and Lewy-body pathology in the substantia nigra displayed a variety of clinical and pathologic syndromes. We now describe a family with very slowly progressive Parkinson's disease (PD) that has, in most cases, responded poorly to levodopa and includes subjective visual difficult. Four personally confirmed cases--with onset at ages 35, 25, 16, and 16-have occurred in three generations, and four suspicious cases have occurred in three other generations. There has been a trend toward progressively younger age of onset. One autopsied case showed a distribution of cell loss and Lewy bodies typical of PD. The hereditary pattern is most compatible with autosomal dominance. This kindred's illness shows that a presumably single Mendelian dominant gene can cause the clinical and pathologic features of PD, and further extends the clinical spectrum of pathologically typical Lewy-body PD.

Olfactory dysfunction occurs in most patients with idiopathic Parkinson's disease (PD). In this study, we sought to determine whether such dysfunction is also present in progressive supranuclear palsy (PSP), a condition which shares a number of motor symptoms with PD and is commonly misdiagnosed as PD. We administered the University of Pennsylvania Smell Identification Test, a standardized test of odor identification ability, to 21 PSP patients; 17 also received a forced-choice odor detection threshold test. We compared the olfactory test scores to those obtained from PD patients and normal controls matched to the PSP patients on the basis of age, sex, and smoking habits. Overall, the olfactory function of the PSP patients was markedly superior to that of the PD patients and did not differ significantly from that of the normal controls. There was no association in either the PSP or PD patient groups between (1) the olfactory test scores and (2) measures of motor symptom severity, disease stage, and medication usage. These findings demonstrate that patients with PSP and PD differ markedly in their ability to smell and suggest that olfactory testing may be useful in their differential diagnosis.

We used a family history questionnaire, semi-structured interview, and personal examination of secondary cases to collect data on the prevalence of Parkinson's disease (PD) in relatives of patients seen consecutively for 1 year and assessed the proportion of secondary cases of PD as a function of pedigree completeness. Survival analysis methods were applied to estimate the lifetime risk and age-at-onset distribution of PD among first-degree relatives of probands. When we considered siblings of probands with affected parents, the cumulative risk increased significantly over siblings of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. We further analyzed 80 multicase families with two or more affected individuals. Age-adjusted segregation ratios approaching 0.5 and similar proportions of affected parents and siblings, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD.

When more really means more: WGS standards and quality control Next-generation sequencing (NGS) is reshaping the landscape of modern genetic diagnostic laboratories and their operational standards. NGS is gradually replacing the single-gene Sanger sequencing with targeted multigene panel-based resequencing for genes with variants implicated in any number of common diseases, from cardiovascular or neurological disorders to cancers or drug treatment response. Further advances in technology are positioning whole exome and ultimately whole genome sequencing (WES and WGS) for common diagnostic use. In a rapidly changing environment, quality control considerations are crucial. In this issue, Stephan White et al. (Hum Mutat 38: 912-921, 2017) discuss the critical steps that are required to properly perform WGS. They emphasize the key differences between WGS and WES, the important variables that need to be taken into serious consideration when performing NGS for both germline and somatic variants, the necessary quality control measures to monitor the entire process, and the standard operation procedures to ensure that NGS services will always be provided in a standardized manner. It is obvious that further technological advances in massively parallel DNA sequencing technology, accompanied by concomitant price reductions, will make WES and WGS more affordable and hence easier to become the ultimate genetic test in molecular diagnosis. Such advances must undoubtedly be accompanied with the necessary health technology assessment and economic evaluation analyses, demonstrating that such approaches are indeed cost-effective so that they can be adopted sooner and, most importantly, are covered by national healthcare systems. The points discussed in White et al., combined with those from recently published guidelines for variant calling, genomic databases, genomic data sharing and translational tools, should facilitate implementation of NGS services into the molecular diagnostic setting for routine clinical care.

Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.