Clinical Classification of Borderline Cases in the Family Study of Essential Tremor: An Analysis of Phenotypic Features

Background: In genetic research on essential tremor (ET), certain individuals may be particularly challenging to categorize diagnostically. Methods: In the Family Study of Essential Tremor (>200 enrollees), 28 participants with borderline clinical findings who did not meet strict criteria for ET were assigned final diagnoses of ET. We scrutinized the clinical features of these cases and the sensitivity/specificity of certain features that best separated them from 19 unaffected individuals. Results: Borderline ET cases differed from unaffected individuals in eight features: total tremor score, at least one kinetic tremor rating ≥1.5, at least one kinetic tremor rating ≥1.5 in the dominant arm, tremor rating during spiral drawing ≥1.5, higher spiral axis score, head tremor, complaint of tremor, and comment on tremor by others. The combination of at least one kinetic tremor rating ≥1.5 in the dominant arm and the presence of at least three of the remaining seven features predicted the clinician‐assigned diagnosis in 88.6% of borderline ET vs. unaffected individuals (sensitivity 84.6%, specificity 94.4%). Discussion: In a family study, a small number of clinical features characterized borderline ET, and a particular combination of these separated the majority of these borderline cases from normals. These analyses may help researchers minimize diagnostic misclassification

Nonparametric estimation of age-at-onset distributions from censored kin-cohort data

SUMMARY We present a nonparametric estimator of genotype-specific age-at-onset distributions from kin-cohort data. Standard error calculations are derived and the methodology is illustrated through an analysis of the influence of mutations of the Parkin gene on Parkinson's disease. Semiparametric efficiency considerations are briefly discussed

Transient, Isolated Head Tremor in “Unaffected” Individuals: Is Essential Tremor an Even More Prevalent Disease Than We Suppose?

Background: Mild and transient head tremor may sometimes be observed in otherwise tremor-free relatives of essential tremor (ET) cases, although its prevalence is unclear. A diagnostic question is whether this transient, isolated head tremor, often observed as no more than a wobble, is an early manifestation of ET or whether it is a normal finding. A direct comparison with controls is needed.Methods: Two hundred and forty-one first-degree relatives of ET cases (FD-ET) and 77 spousal controls (Co) were enrolled in a study of ET. Each underwent a detailed evaluation that included a tremor history and videotaped neurological examination. None of the enrollees reported tremor, had a prior diagnosis of ET, or had significant tremor on screening spirals. All videotaped examinations were initially reviewed by a movement disorder neurologist blinded to subject type, and among those with head tremor on examination, co-reviewed by two additional movement disorders neurologists.Results: Twenty-six (10.8, 95% Confidence interval [CI] = 7.5–15.3%) of 241 FD-ET vs. 2 (2.6, 95% CI = 0.7–9.0%) of 77 Co had isolated, transient head tremor (odds ratio = 4.54, 95% CI = 1.05–19.57, p = 0.04). No enrollee had significant upper extremity tremor and none met inclusion criteria for ET based on the presence of upper extremity tremor. With one exception, head tremor occurred during or after phonation. It was always transient (generally a single back and forth wobble) and rare (observed briefly on one or two occasions during the videotaped examination) and had a faster frequency, lower amplitude and a different quality than voluntary head shaking.Conclusion: The basis for the observed isolated head tremor is unknown, but it could be an early feature of ET in ET families.Indeed, one-in-ten otherwise unaffected first-degree relatives of ET cases exhibited such tremor. To a far lesser extent it was also observed in “unaffected” controls. In both, it is likely a sign of early, emerging, undiagnosed ET, although follow-up studies are needed to confirm this. If it were ET, it would indicate that the prevalence of ET may be considerably higher than previously suspected

Software Citation Implementation Challenges

The main output of the FORCE11 Software Citation working group (https://www.force11.org/group/software-citation-working-group) was a paper on software citation principles (https://doi.org/10.7717/peerj-cs.86) published in September 2016. This paper laid out a set of six high-level principles for software citation (importance, credit and attribution, unique identification, persistence, accessibility, and specificity) and discussed how they could be used to implement software citation in the scholarly community. In a series of talks and other activities, we have promoted software citation using these increasingly accepted principles. At the time the initial paper was published, we also provided guidance and examples on how to make software citable, though we now realize there are unresolved problems with that guidance. The purpose of this document is to provide an explanation of current issues impacting scholarly attribution of research software, organize updated implementation guidance, and identify where best practices and solutions are still needed

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

Fetal hemoglobin level is a heritable complex trait that strongly correlates with the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease

Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method

Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis

Case-control study of the parkin gene in early-onset Parkinson disease

Background: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. Objective: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged 50 years) and controls participating in a familial aggregation study. Patients and Methods: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. Results: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. Conclusions: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD

PCDH10 Promoter Hypermethylation is Frequent in most Histologic Subtypes of Mature Lymphoid Malignancies and Occurs Early in Lymphomagenesis

PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well-characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T-cell lymphoma specimens and cell lines. These findings were further validated by Sequenom Mass-array analysis. Promoter hypermethylation was also identified in 28.6% cases of reactive follicular hyperpla- sia, more commonly occurring in states of immune deregulation and associated with rare presence of clonal karyotypic aberrations, suggesting that PCDH10 methylation occurs early in lymphomagenesis. PCDH10 expression was down regu- lated via promoter hypermethylation in T- and B-cell lymphoma cell lines. The transcriptional down-regulation resulting from PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases in cell lines. Both T- and B-cell lymphoma cell lines harboring methylation-mediated inactivation of PCDH10 were resistant to doxorubicin treatment, suggesting that hypermethylation of this gene might contribute to chemotherapy response

Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

Objective Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. Methods We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by ‘gene wise’ genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. Results In a ‘gene-wise’ analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03–4.14 x10-5). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Interpretation Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies