Nathaniel R. Whaley

Parkinson disease Handedness predicts asymmetry

Objective: To determine the proportion of individuals in a clinic-based setting that present with asymmetric Parkinson disease (PD) and identify predictive factors associated with asymmetric symptoms. Methods: The authors examined right vs left difference scores on the Unified Parkinson Disease Rating Scale motor subscale in a consecutive clinical series of 1,277 individuals diagnosed with PD. Predictors of asymmetry included sex, symptomatic disease duration, age at onset, initial motor symptom laterality, handedness, and medical history variables (e.g., family history of PD). Results: Nearly half the sample (46%) met criteria for asymmetric disease based on a right vs left difference score of ≥5 points, and 12% of the sample had a difference score of ≥10 (difference score: mean = 4, SD = 3.4). All three cardinal features of PD showed characteristics of asymmetric disease presentation. Multiple regression analyses showed that an increased discrepancy between right- and left-sided symptoms was significantly associated with a shorter disease duration, younger age at symptomatic onset, asymmetric initial symptom onset, hand dominance, and a positive self-reported family history of “other” neurodegenerative disorder. Hand dominance was related to the side of asymmetric disease such that left-handed individuals tended to have more severe disease on the left side of the body. Conclusion: Asymmetric presentation of Parkinson disease features was a common occurrence in the clinical cohort. Asymmetry was reliably predicted by several clinical characteristics, although the moderate level of explained variance (i.e., between 16 and 23%) highlighted the need for additional research examining predictive models of asymmetric disease. Recommendations for the classification and measurement of asymmetric disease are discussed.

Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.

Gender and the Parkinson’s disease phenotype

AbstractObjectivesTo determine whether there are gender differences in the Parkinson’s disease (PD) phenotype using a large clinic–based cohort.MethodsWe examined gender differences in demographic, historical and clinical characteristics in a consecutive clinical series of 1264 individuals diagnosed with PD.ResultsThe majority of individuals in the sample were male (67 %). Comparative analyses showed males and females were not significantly different on most demographic and historical characteristics. For both genders, the mean age and the mean age at symptomatic onset were about 70 and 63 years, respectively and, thus, disease duration was not significantly different between genders. The proportion of individuals with a positive family history of PD (15 %) was similar for both genders. A positive history of depression was significantly higher in females (35 % vs. 24 %). The UPDRS instability score was significantly worse among females, whereas the rigidity score was significantly worse for males. Females showed significantly worse ADL capacity and a more advanced H&Y stage. The proportion of individuals receiving antiparkinsonian medication (about 66 %) and time between the last dose and the clinical evaluation (about 4 hours) was similar for both genders. There was a trend for lower daily levodopa equivalence dosage and more severe dyskinesia score among females but these differences did not reach statistical significance after Bonferroni correction.ConclusionsThe majority of comparisons tended to highlight the commonalities in the PD phenotype between genders, particularly in reference to historical and early disease stage characteristics. However, gender may be an important factor related to the expression of PD features during the symptomatic disease course.

Clinical and pathologic features of families with LRRK2-associated Parkinson’s disease

The etiology for Parkinsons disease (PD) remains unknown. Genetic causes have been identified with several distinct mutations. Recently, 9 mutations involving a novel gene, leucine-rich repeat kinase 2 (LRRK2), have been identified as the cause of autosomal dominant PD in kindreds, with some of them previously linked to the PARK8 locus on chromosome 12. LRRK2 mutations are relatively common genetic causes of familial and sporadic PD. In addition, these mutations have been identified in diverse populations. The clinical and pathologic features of LRRK2-associated PD are indistinguishable from idiopathic PD; however, considerable clinical and pathologic variability exists even among kindreds. This short review highlights the clinical and pathologic features in LRRK2-associated parkinsonism.

Three sib-pairs of autopsy-confirmed progressive supranuclear palsy

OBJECTIVE To describe the clinical, pathological, and genetic features of three sib-pairs of pathologically-confirmed progressive supranuclear palsy (PSP). METHODS We searched the Mayo Clinic neurodegenerative diseases brain bank for cases of PSP in which more than one family member had pathologically-confirmed PSP. Clinical and pathological data were reviewed and all individuals were screened for mutations in MAPT, by sequencing exons 1, 7, and 9-13. RESULTS We identified three sib-pairs of pathologically-confirmed PSP. Sufficient information was available to suggest an autosomal dominant inheritance in two. The mean age at symptom onset was 41 years in one pair, and 76 years in the other two. The young onset pair had a p.S285R mutation in MAPT, but no mutations were detected in the other two. CONCLUSIONS All sib-pairs had typical pathological features of PSP; however, the age at onset of the sib-pair with MAPT mutation was significantly younger than sporadic PSP. Future studies are warranted to identify a possible genetic basis for PSP associated with late onset and typical PSP pathology.

Myokymic discharges in amyotrophic lateral sclerosis (ALS): a rare electrophysiologic finding?

Myokymic discharges (MDs) are uncommonly recognized in amyotrophic lateral sclerosis (ALS). The electrophysiologic findings in 96 ALS patients were retrospectively reviewed. MDs were found in 5.2% of patients, in 0.81% of total muscles examined (8.2% cranial muscles vs. 0.15% limb muscles). The higher frequency of MDs in cranial muscles suggests a difference in the metabolic environment or other mechanism of instability of the anterior horn cells in the brainstem compared to the spinal cord. Muscle Nerve 41: 107–109, 2010

Progressive supranuclear palsy: phenotypic sex differences in a clinical cohort.

We examined sex‐based differences in phenotypic expression among a consecutive clinical series of 121 individuals diagnosed with probable progressive supranuclear palsy (PSP). For both men (44%) and women (56%), the age at symptomatic onset (66.2 and 68.5 years, respectively) and disease duration (4.6 and 4.3 years, respectively) were similar. The overwhelming majority of sex‐based comparisons showed no significant difference on a variety of demographic, historical, and clinical characteristics, as well as measures of disease progression. The only differences observed were that men had significantly worse tremor as measured by the Unified Parkinsons Disease Rating Scale tremor subscore (0.9 for men and 0.3 for women, P < 0.01) and men had a significantly higher mean body mass index (BMI; 28.2 for men and 25.1 for women, P = 0.01), although these differences were not significant after Bonferroni correction. In general, the disease phenotype was similar between men and women, suggesting that sex may have little or no influence on the development, expression, or progression of the PSP phenotype.

Lower tibial than peroneal compound muscle action potential amplitude in neuromuscular diseases.

The pattern of findings on nerve conduction studies is an important component of an electrodiagnostic evaluation to assess for peripheral neuromuscular disorders. The aim of this study was to determine the extent to which a lower tibial compound muscle action potential (CMAP) amplitude compared with the peroneal CMAP amplitude is more indicative of specific neuromuscular disorders such as S1 radiculopathies, sciatic neuropathies, or peripheral neuropathies. The electromyographic (EMG) findings of 921 patients who had undergone an EMG of the lower extremity and in whom the EMG study was interpreted as normal or a single neuromuscular diagnosis was identified were retrospectively reviewed to determine the frequency of an absolutely lower tibial than peroneal CMAP amplitude. Thirty-five (7%) healthy subjects had a lower tibial than peroneal CMAP amplitude (i.e., the absolute value of the tibial CMAP was lower than the absolute value of the peroneal CMAP), despite both values being in normal range. The finding on nerve conduction study of an absolutely lower tibial than peroneal CMAP occurred in a significantly higher proportion of patients with a diffuse polyneuropathy (24%) and S1 radiculopathies (21%) compared with controls. The findings suggest that in subjects in whom lower extremity nerve conduction study demonstrates an absolutely lower tibial than peroneal CMAP amplitude, neuromuscular disorders such as a polyneuropathy or S1 radiculopathy should be considered.