Depression Reduces Accuracy While Parkinsonism Slows Response Time for Processing Positive Feedback in Patients with Parkinson's Disease with Comorbid Major Depressive Disorder Tested on a Probabilistic Category-Learning Task.

Major depressive disorder (MDD) is the most common non-motor manifestation of Parkinson's disease (PD) affecting 50% of patients. However, little is known about the cognitive correlates of MDD in PD. Using a computer-based cognitive task that dissociates learning from positive and negative feedback, we tested four groups of subjects: (1) patients with PD with comorbid MDD, (2) patients with PD without comorbid MDD, (3) matched patients with MDD alone (without PD), and (4) matched healthy control subjects. Furthermore, we used a mathematical model of decision-making to fit both choice and response time data, allowing us to detect and characterize differences between the groups that are not revealed by cognitive results. The groups did not differ in learning accuracy from negative feedback, but the MDD groups (PD patients with MDD and patients with MDD alone) exhibited a selective impairment in learning accuracy from positive feedback when compared to the non-MDD groups (PD patients without MDD and healthy subjects). However, response time in positive feedback trials in the PD groups (both with and without MDD) was significantly slower than the non-PD groups (MDD and healthy groups). While faster response time usually correlates with poor learning accuracy, it was paradoxical in PD groups, with PD patients with MDD having impaired learning accuracy and PD patients without MDD having intact learning accuracy. Mathematical modeling showed that both MDD groups (PD with MDD and MDD alone) were significantly slower than non-MDD groups in the rate of accumulation of information for stimuli trained by positive feedback, which can lead to lower response accuracy. Conversely, modeling revealed that both PD groups (PD with MDD and PD alone) required more evidence than other groups to make responses, thus leading to slower response times. These results suggest that PD patients with MDD exhibit cognitive profiles with mixed traits characteristic of both MDD and PD, furthering our understanding of both PD and MDD and their often-complex comorbidity. To the best of our knowledge, this is the first study to examine feedback-based learning in PD with MDD while controlling for the effects of PD and MDD.

Multiplex families with epilepsy: Success of clinical and molecular genetic characterization.

OBJECTIVE: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. METHODS: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate. RESULTS: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. CONCLUSION: A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.

Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia.

We studied a consanguineous Palestinian Arab family segregating an autosomal recessive progressive myoclonus epilepsy (PME) with early ataxia. PME is a rare, often fatal syndrome, initially responsive to antiepileptic drugs which over time becomes refractory and can be associated with cognitive decline. Linkage analysis was performed and the disease locus narrowed to chromosome 19p13.3. Fourteen candidate genes were screened by conventional Sanger sequencing and in one, LMNB2, a novel homozygous missense mutation was identified that segregated with the PME in the family. Whole exome sequencing excluded other likely pathogenic coding variants in the linked interval. The p.His157Tyr mutation is located in an evolutionarily highly conserved region of the alpha-helical rod of the lamin B2 protein. In vitro assembly analysis of mutant lamin B2 protein revealed a distinct defect in the assembly of the highly ordered fibrous arrays typically formed by wild-type lamin B2. Our data suggests that disruption of the organisation of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, causes the epilepsy and early ataxia syndrome and extends the aetiology of PMEs to include dysfunction in nuclear lamin proteins.

Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.

OBJECTIVE: To present the clinical, molecular, and cell biological findings in a family with an autosomal recessive form of hereditary spastic paraplegia characterized by a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN). METHODS: We used a combination of whole-genome linkage analysis and exome sequencing to map the disease locus and to identify the responsible gene. To analyze the physiologic consequences of the disease, we used biochemical and cell biological methods. RESULTS: Ten members of a highly consanguineous family manifested a childhood-onset SPOAN-like phenotype with slow progression into late adulthood. We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor splice-site mutation in the IBA57 gene, previously implicated in 2 infants with lethal perinatal encephalomyopathy. This gene encodes the mitochondrial iron-sulfur (Fe/S) protein assembly factor IBA57. In addition to a severely decreased amount of normal IBA57 messenger RNA, a patient's cells expressed an aberrantly spliced messenger RNA with a premature stop codon. Lymphoblasts contained 10-fold-lower levels of wild-type, but no signs of truncated IBA57 protein. The decrease in functional IBA57 resulted in reduced levels and activities of several mitochondrial [4Fe-4S] proteins, including complexes I and II, while mitochondrial [2Fe-2S] proteins remained normal. CONCLUSIONS: Our findings reinforce the suggested specific function of IBA57 in mitochondrial [4Fe-4S] protein maturation and provide additional evidence for its role in human disease. The less decreased IBA57 protein level in this family explains phenotypic differences compared with the previously described lethal encephalomyopathy with no functional IBA57.

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa.

Depression impairs learning whereas anticholinergics impair transfer generalization in Parkinson patients tested on dopaminergic medications.

In a study of acquired equivalence in Parkinson disease (PD), in which patients were tested on normal dopaminergic medication, we found that comorbid clinical depression impairs initial acquisition, whereas the use of anticholinergic therapy impairs subsequent transfer generalization. In addition, this study provides a replication of the basic finding of Myers et al (2003) that patients with PD on dopaminergic therapy are impaired at initial acquisition, but normal at subsequent transfer generalization, generalizing these results to an Arabic-speaking population including many participants with no formal education. These results are consistent with our past computational modeling, which argues that acquisition of incrementally acquired, feedback-based learning tasks is dependent on cortico-striatal circuits, whereas transfer generalization is dependent on medial temporal (MT) structures. They are also consistent with prior computational modeling, and with empiric work in humans and animals, suggesting that anticholinergic drugs may particularly impair cognitive abilities that depend on the MT lobe.

Founder effect with variable age at onset in Arab families with Lafora disease and EPM2A mutation.

PURPOSE: We observed three apparently unrelated and geographically separate Arab families with Lafora disease in Israel and the Palestinian territories. METHODS: We clinically evaluated the families and analyzed their DNA for EPM2A mutations. RESULTS: Of seven individuals with Lafora disease, the clinical onset varied from 13 to 20 years. All three families shared the same novel homozygous deletion in EPM2A. Haplotype analysis around the deletion showed that the families shared a common homozygous haplotype. The boundaries of this haplotype varied between families and even within one family. CONCLUSIONS: We conclude that considerable variability in the age at onset of Lafora disease can occur within families. Identical mutations can be associated with the classic adolescent presentation, as well as late-onset cases. Haplotype analysis suggests that this EPM2A mutation arose many generations previously, so it may be of importance for cases distributed more widely in the Middle East.