Kishore R. Kumar

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene

A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family.

Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort

Objective: To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD). Methods: This is a large single-center study of the DeNoPa cohort, including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis. Results: Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI] 0.878–0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886–0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943–0.982). Conclusions: We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of >0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.

Two Australian families with inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia: novel clinical and genetic findings

We report the first Australian families with inclusion-body myopathy, Pagets disease of the bone and frontotemporal dementia (IBMPFD). The clinical characteristics of the two pedigrees are described including a previously undescribed phenotypic feature of pyramidal tract dysfunction in one family member. A novel mutation in the valosin-containing protein (VCP) gene (p.Arg155Leu) was found in one family while the other family had a previously reported mutation (p.Leu198Trp). Our findings broaden the phenotypic spectrum of IBMPFD and further emphasise the resemblance to amyotrophic lateral sclerosis in some cases.

Genetics of Parkinson disease and other movement disorders.

PURPOSE OF REVIEW We will review the recent advances in the genetics of Parkinson disease and other movement disorders such as dystonia, essential tremor and restless legs syndrome (RLS). RECENT FINDINGS Mutations in VPS35 were identified as a novel cause of autosomal dominant Parkinson disease using exome sequencing. Next generation sequencing (NGS) was also used to identify PRRT2 mutations as a cause of paroxysmal kinesigenic dyskinesia (DYT10). Using a different technique, that is linkage analysis, mutations in EIF4G1 were implicated as a cause of Parkinson disease and mutations in SLC20A2 as a cause of familial idiopathic basal ganglia calcification. Furthermore, genome-wide association studies (GWAS) and meta-analyses have confirmed known risk genes and identified new risk loci in Parkinson disease, RLS and essential tremor. New models to study genetic forms of Parkinson disease, such as stem cell-derived neurons, have helped to elucidate disease-relevant molecular pathways, such as the molecular link between Gaucher disease and Parkinson disease. SUMMARY New genes have been implicated in Parkinson disease and other movement disorders through the use of NGS. The identification of risk variants has been facilitated by GWAS and meta-analyses. Furthermore, new models are being developed to study the molecular mechanisms involved in the pathogenesis of these diseases.

Mutations in GNAL: A Novel Cause of Craniocervical Dystonia

IMPORTANCE Mutations in the GNAL gene have recently been shown to cause primary torsion dystonia. The GNAL-encoded protein (Gαolf) is important for dopamine D1 receptor function and odorant signal transduction. We sequenced all 12 exons of GNAL in 461 patients from Germany, Serbia, and Japan, including 318 patients with dystonia (190 with cervical dystonia), 51 with hyposmia and Parkinson disease, and 92 with tardive dyskinesia or acute dystonic reactions. OBSERVATIONS We identified the following two novel heterozygous putative mutations in GNAL: p.Gly213Ser in a German patient and p.Ala353Thr in a Japanese patient. These variants were predicted to be pathogenic in silico, were absent in ethnically matched control individuals, and impaired Gαolf coupling to D1 receptors in a bioluminescence energy transfer (BRET) assay. Two additional variants appeared to be benign because they behaved like wild-type samples in the BRET assay (p.Ala311Thr) or were detected in ethnically matched controls (p.Thr92Ala). Both patients with likely pathogenic mutations had craniocervical dystonia with onset in the fifth decade of life. No pathogenic mutations were detected in the patients with hyposmia and Parkinson disease, tardive dyskinesias, or acute dystonic reactions. CONCLUSIONS AND RELEVANCE Mutations in GNAL can cause craniocervical dystonia in different ethnicities. The BRET assay may be a useful tool to support the pathogenicity of identified variants in the GNAL gene.

Genetics of Parkinson's Disease

The identification of genes contributing to Parkinsons disease (PD) has allowed for an improved understanding of the underlying pathogenesis of the disorder. The authors review the rapidly growing field of PD genetics, with a focus on the clinical, genetic, and pathophysiologic features of well-validated monogenic forms of PD caused by mutations in the SNCA, LRRK2, PARKIN, PINK1, DJ-1, and ATP13A2 genes. In addition, they discuss mutations in the GBA gene, which increase susceptibility for PD. The authors also evaluate the implications of genome-wide association studies and stem cell-derived disease models and give recommendations for genetic testing.

Glucocerebrosidase mutations in a Serbian Parkinson's disease population.

To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinsons disease (PD) population.

Two Faces of the Same Coin: Benign Familial Infantile Seizures and Paroxysmal Kinesigenic Dyskinesia Caused by PRRT2 Mutations

S huzo Kure, the first to describe paroxysmal kinesigenic dyskinesia (PKD) in a Japanese journal in 1892, would have been pleased to learn that the gene for this condition has now been identified. Paroxysmal kinesigenic dyskinesia is the most common paroxysmal movement disorder, presenting with brief episodes of dystonic, choreatic, or ballistic, and sometimes bizarre, involuntary movements triggered by sudden movement with onset in childhood or adolescence. Owing to its unusual semiology, PKD is often misdiagnosed as a psychogenic disorder. However, it is easily treatable with low doses of anticonvulsants. Notably, PKD has been clinically and genetically linked to a variety of heterogeneous and, at first sight, unrelated conditions. This includes benign familial infantile seizures (BFIS); the syndrome of rolandic epilepsy, paroxysmal exercise–induced dyskinesia, and writer’s cramp; and even the trait of wet ear wax (cerumen). Indeed, the co-occurrence of BFIS and PKD in families has resulted in the identification of another illness, infantile convulsions and paroxysmal choreo-athetosis (ICPC). Benign familial infantile seizures may be one of the most common forms of epilepsy that develop in the first 2 years of life and is characterized by nonfebrile convulsions with onset at between 3 and 12 months of age. Seizures are focal, with or without secondary generalization, occurring in clusters and often resulting in cyanosis. The disorder leads to considerable anxiety among parents and doctors who are unfamiliar with it, but it also responds reliably to carbamazepine and has a benign prognosis. Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene, which is located within the previously linked region on chromosome 16, have been identified as the cause of PKD and ICPC. We screened the entire PRRT2 gene for mutations in 3 families with ICPC and 1 family with PKD—3 of German and 1 of Turkish-Russian descent. Neuropediatricians reviewed the patients, and the diagnoses of PKD and BFIS were based on established criteria. All affected members had typical features of PKD and/or BFIS and were identified with the previously reported heterozygous truncating c.649dupC (p.R217PX8) mutation. Notably, this mutation was found in 3 individuals with isolated BFIS, 6 patients with pure PKD, 3 with both BFIS and PKD, and 1 nonmanifesting carrier (Figure). Genotyping of these pedigrees showed 4 independent haplotypes, suggesting that this mutation arose from recurrent mutational events. These results confirm that PRRT2 mutations cause PKD and ICPC in multi-ethnic populations including German, Turkish, and Russian. Most importantly, they provide further evidence that the 2 apparently clinically distinct syndromes of BFIS and PKD can be allelic conditions, and they can both be caused by the same mutation in PRRT2. There has been debate about whether paroxysmal dyskinesias have an epileptic origin. It is notable that in PKD, ictal and interictal changes are typically absent on electroencephalogram. However, the confirmation that PKD and BFIS can have a shared genetic cause lends support to the concept that the pathophysiological mechanism underlying PKD may be subcortical epileptogenic discharges, possibly originating from the basal ganglia. The molecular pathway may involve synaptic regulation via interactions with the SNAP25 protein, ultimately leading to neuronal hyperexcitability. These findings are of interest to a broad range of clinicians who may encounter patients presenting with infantile convulsions or PKD. Paroxysmal kinesigenic dyskinesia should be suspected in families with a child with BFIS and vice versa. There is now evidence to suggest that a simple genetic test (sequencing of the small PRRT2 gene) may replace laborious and expensive diagnostic investigations in these patients. The finding of PRRT2 mutations in families with isolated BFIS without cooccurring PKD has been a recent development, further expanding the phenotypic spectrum.

A Novel OPA3 Mutation Revealed by Exome Sequencing: An Example of Reverse Phenotyping

IMPORTANCE We sought to unravel the genetic cause in a consanguineous Pakistani family with a complex neurological phenotype. OBSERVATIONS Neurological and ophthalmological examination, including videotaping and fundoscopy, and genetic investigations, including homozygosity mapping and exome sequencing, were performed at the University of the Punjab and the University of Lübeck. Participants included 2 severely affected cousins from consanguineous parents, 10 of their reportedly unaffected relatives, and 342 Pakistani controls. Motor symptoms in the 2 patients started at the age of 3 to 4 years and included chorea, cerebellar ataxia, dystonia, and pyramidal tract signs. Genome-wide genotyping delineated 2 regions of homozygosity on chromosomes 13q12.11 to 13q12.13 and 19q12 to 19q13.41. Exome sequencing revealed 2 rare, homozygous variants (c.32 T>A [p.L11Q] in OPA3 and c.941 C>G [p.A314G] in TSHZ3) that segregated with the disease. Only the OPA3 variant was absent in the control subjects and predicted to be damaging. Subsequent ophthalmological assessment revealed bilateral optic atrophy in both patients. CONCLUSIONS AND RELEVANCE Mutations in OPA3 have been reported in Costeff optic atrophy syndrome. We identify a novel missense mutation in OPA3 as the cause of a complex neurological disorder, expanding the OPA3 -linked phenotype by early-onset pyramidal tract signs and marked lower limb dystonia. Investigation of optic atrophy was initiated only after genetic analysis, a phenomenon referred to as reverse phenotyping.

Depression and Quality of Life in Monogenic Compared to Idiopathic, Early-Onset Parkinson's Disease

Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early‐onset PD cases, 21% of late‐onset cases, and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson‐associated depression reported fewer feelings of guilt or self‐doubt than treated controls, but the occurrence of suicidal ideation was associated with severity of depression only. Social phobia (P = 0.018) and agoraphobia (P = 0.059) were more common in manifesting carriers than in any other group. QoL was decreased in the Parkinson groups, particularly in the early‐onset cases (P < 0.001), and QoL correlated with depression in all analyses. In our study, monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further optimized.