The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family.

Tourette Disorder (TD) is a childhood-onset neuropsychiatric and neurodevelopmental disorder characterized by the presence of both motor and vocal tics. The genetic architecture of TD is believed to be complex and heterogeneous. Nevertheless, DNA sequence variants co-segregating with TD phenotypes within multiplex families have been identified. This report examines whole exomes of affected and unaffected individuals in a multiplex TD family to discover genes involved in the TD etiology. We performed whole exome sequencing on six out of nine members in a three-generation TD multiplex family. Putative deleterious sequence variants co-segregating with TD patients were identified by our in-house bioinformatics pipeline. Induced pluripotent stem cells (iPSCs) were generated from one unaffected and two TD affected individuals. Neurons were derived from the iPSCs and biochemical assays were conducted to evaluate possible molecular differences between affected and unaffected. A rare heterozygous nonsense mutation in PNKD was co-segregated with TD in this multiplex family. Transcript and protein levels of the PNKD long isoform were reduced in neurons derived from the individuals with TD due to the nonsense mutation, indicating nonsense-mediated mRNA decay. We demonstrated that the PNKD long isoform monomer oligomerizes with itself as well as interacts with the synaptic active zone protein RIMS1α. We concluded that reduced PNKD long isoform levels are detected in all affected individuals and we provide evidence for a mechanism whereby this might contribute to the TD phenotype.

A study of idiopathic torsion dystonia in a non-Jewish family: evidence for genetic heterogeneity.

A gene (DYT1) for idiopathic torsion dystonia (ITD) was mapped to chromosome 9q34 in non-Jewish and Jewish families; the dystonia in these families usually began in childhood, with the limb muscles affected first. The role of the DYT1 gene in adult-onset and cervical- or cranial-onset ITD is unknown. We examined 53 individuals from four generations of a non-Jewish North American family with adult-onset ITD. There were seven affected family members, with a mean age at onset of 28.4 years (range, 7 to 50 years). In six of the seven, the neck was affected first. All seven developed cervical dystonia, and dysarthria or dysphonia occurred in five. Linkage data excluded the region containing the DYT1 locus, indicating that DYT1 was not responsible for ITD in this family. This study provides evidence that a gene other than DYT1 is responsible for some cases of adult cervical-onset dystonia.

Investigation of dopamine receptor (DRD4) and dopamine transporter (DAT) polymorphisms for genetic linkage or association to panic disorder.

Clinical and animal studies suggest a role for the neurotransmitter dopamine in anxiety states. In humans, one such condition is panic disorder, which is typified by recurrent panic attacks accompanied by anticipatory anxiety. Family, segregation, and twin studies imply a genetic component to the pathophysiology of panic disorder. In this study, we examined the genes for the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) using three common sequence polymorphisms. Two of these polymorphisms were in DRD4, a 12 base-pair insertion/deletion in exon 1 and a 48 base-pair repeat in exon 3, and the third was a 40 base-pair repeat in the 3' untranslated region of DAT. We employed a family-based design, using 622 individuals in 70 families, as well as 82 haplotype relative risk "trios". Subjects were genotyped at the polymorphic loci, and the data were analyzed for genetic association and linkage. There were no significant differences in allele frequencies or occurrence of genotypes within the triads for any of the three polymorphisms. No significant linkage between the DRD4 or DAT polymorphisms and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. However, LOD scores of approximately 1.1 and 1.05 were observed for the DAT and DRD4 exon 1 loci, respectively. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Results of a genome-wide genetic screen for panic disorder.

Panic disorder is characterized by spontaneous and recurrent panic attacks, often accompanied by agoraphobia. The results of family, twin, and segregation studies suggest a genetic role in the etiology of the illness. We have genotyped up to 23 families that have a high density of panic disorder with 540 microsatellite DNA markers in a first-pass genomic screen. The thirteen best families (ELOD > 6.0 under the dominant genetic model) have been genotyped with an ordered set of markers encompassing all the autosomes, at an average marker density of 11 cM. Over 110,000 genotypes have been generated on the whole set of families, and the data have been analyzed under both a dominant and a recessive model, and with the program SIBPAIR. No lod scores exceed 2.0 for either parametric model. Two markers give lod scores over 1.0 under the dominant model (chromosomes 1p and 20p), and four do under the recessive model (7p, 17p, 20q, and X/Y). One of these (20p) may be particularly promising. Analysis with SIBPAIR yielded P values equivalent to a lod score of 1.0 or greater (i.e., P < .016, one-sided, uncorrected for multiple tests) for 11 marker loci (2, 7p, 8p, 8q, 9p, 11q, 12q, 16p, 20p and 20q).

Age-at-interview bias in anticipation studies: computer simulations and an example with panic disorder.

The phenomenon of anticipation has received considerable interest recently, especially among researchers investigating the genetics of psychiatric disorders. Anticipation can involve an earlier age at onset, greater severity, and/or a higher number of affected individuals in successive generations within a family. There is some controversy concerning detection of age-at-onset anticipation, due to problems of sampling bias, which may account for the phenomenon by preferentially sampling either lateronset parents or earlier-onset children. One source of bias that has not been explicitly investigated is differential age at interview between parent and child, such that parents have passed through more of the risk period than their offspring. We conducted a computer simulation study of affected parent-child pairs to determine whether, for realistic age-at-onset and age-at-interview distributions, this source of bias is a serious one. Our results show that the timing of diagnostic assessment can strongly affect the ascertainment of parent-child pairs, to produce a severely biased sample exhibiting apparent anticipation. Under realistic assumptions, an investigator may face a greatly increased risk of false positives (i.e. detecting anticipation when none exists). For example, a nominal 5% significance level may correspond to true p values as high as 50% or even approaching 100%. We conclude with an application to existing data on panic disorder.

Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder.

Given the efficacy of medications that interact with the serotonin transporter (5-HTT) in the treatment of panic disorder, we have used a family-based design to test for genetic association and linkage between panic disorder and a functional polymorphism in the promoter of the gene for 5-HTT. In this study, 340 individuals in 45 families, as well as 74 haplotype relative risk 'trios' were genotyped at the polymorphic locus, which consists of a 44 base pair deletion/insertion. There were no significant differences in allele frequencies or occurrence of genotypes within the triads. No linkage between the 5-HTT polymorphism and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. Recent reports suggest an association between the 5-HTT polymorphism and anxiety-related traits, as measured with personality assessment. The results reported here provide evidence that the genetic basis of panic disorder may be distinct from anxiety-related traits assessed by personality inventories in normal populations.

Myoclonus-dystonia, obsessive-compulsive disorder, and alcohol dependence in SGCE mutation carriers.

Although myoclonus and dystonia are the hallmarks of myoclonus-dystonia (M-D), psychiatric features, particularly obsessive-compulsive disorder and alcohol dependence, have been reported in three families linked to chromosome 7q21. As the epsilon sarcoglycan (SGCE) gene for M-D was subsequently identified, we evaluated the relationship between psychiatric features and SGCE mutations in these original and two additional families and confirm that OCD and alcohol dependence are associated with manifesting mutated SGCE.

Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia.

Dopa-responsive dystonia (DRD) is one form of childhood-onset idiopathic torsion dystonia. Adult-onset parkinsonism has appeared in several previously unaffected members in families with DRD suggesting that this may be an additional phenotypical expression of the disease. We report a family with DRD in which 2 women and 1 man, unaffected by dystonia, developed tremor-onset parkinsonism after age 50 years. The women continue on a low dosage of levodopa after 9 and 13 years of treatment, with a stable, nearly complete, symptomatic response. This contrasts to the typical long-term treatment complications observed in patients with Parkinson's disease. We assessed nigrostriatal dopaminergic function in the proband, with typical DRD, and the 2 women with parkinsonism using 6-[18F]fluoro-L-dopa positron emission tomography. All 3 had normal striatal 6-[18F]fluoro-L-dopa uptake. These observations provide compelling evidence that "benign" adult-onset parkinsonism may be an expression of the disease in some members of families with DRD and does not support consideration of the DRD gene as a risk factor for development of Parkinson's disease. There may be considerable clinical heterogeneity in DRD depending on the age at onset.

Increased risk for recurrent major depression in DYT1 dystonia mutation carriers.

BACKGROUND: Prior studies suggest that dystonia is comorbid with affective disorders. This comorbidity could be a reaction to a chronic debilitating disorder or expression of a predisposing gene. The authors took advantage of the identification of a gene for dystonia, DYT1, to test these alternative explanations. METHODS: The authors administered a standardized psychiatric interview to members of families with an identified DYT1 mutation. The authors classified family members into three groups: mutation carriers with dystonia (manifesting carriers; n = 96), mutation carriers without dystonia (non-manifesting carriers; n = 60), and noncarriers (n = 65). RESULTS: The risk for recurrent major depressive disorder was increased in both non-manifesting carriers (RR = 4.95, CI = 1.72 to 14.29) and manifesting carriers (RR = 3.62, CI = 1.00 to 10.53) compared with noncarriers. Mutation carriers also had earlier age at onset of recurrent major depressive disorder than noncarriers. The severity of motor signs was not associated with the likelihood of recurrent depression. Mutation carriers did not have an increased risk for other affective disorders, such as single major depression or bipolar disorder. CONCLUSIONS: Early-onset recurrent major depression is associated with the DYT1 GAG mutation and this association is independent of motor manifestations of dystonia. These findings suggest that early-onset recurrent depression is a clinical expression of the DYT1 gene mutation.

The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-Jews.

Idiopathic torsion dystonia (ITD) is characterized by involuntary twisting movements and postures. A gene for this disorder, DYT1, was mapped to chromosome 9q34 in 12 Ashkenazi Jewish (AJ) families and one large non-Jewish kindred. In the AJ population, strong linkage disequilibrium exists between DYT1 and adjacent markers within a 2-cM region. The associated haplotype occurs in > 90% of early limb-onset AJ cases. We examined seven non-Jewish ITD families of northern European and French Canadian descent to determine the extent to which early-onset ITD in non-Jews maps to DYT1. Results are consistent with linkage to the DYT1 region. Affected individuals in these families are clinically similar to the AJ cases; i.e., the site of onset is predominantly in the limbs and at least one individual in each pedigree had onset before age 12 years. None carries the AJ haplotype; therefore, they probably represent different mutations in the DYT1 gene. The two French Canadian families, however, display the same haplotype. Estimates of penetrance in non-Jewish families range from .40 to .75. We identified disease gene carriers and, with adjustments for age at onset, obtained a direct estimate of penetrance of .46. This is consistent with estimates of 30%-40% in the AJ population. Two other non-Jewish families with atypical ITD (later onset and/or cranial or cervical involvement) are not linked to DYT1, which indicates involvement of other genes in dystonia.

No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder.

Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise non-significant. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Exclusion of the DYT1 locus in a non-Jewish family with early-onset dystonia.

The DYT1 gene on chromosome 9q34 underlies idiopathic torsion dystonia (ITD) in Jewish and non-Jewish families with childhood and adolescent-onset dystonia that usually starts in a limb, spreads to other limbs, and uncommonly involves cranial muscles. We examined 39 members of a Mennonite family of German ancestry in which seven were affected with ITD. Age at onset was 14.7 years (range 5-34 years) and symptoms began in a limb in four. The remaining three had onset in the neck, face, and larynx. Dystonia progressed to involve at least one arm and one leg in all seven and there was cranial involvement in six. Five of these six had moderate or severe speech impairment. Linkage analysis with 9q34 markers excluded the region containing the DYT1 locus in this family. This study suggests that a gene other than DYT1 underlies some cases of early limb-onset ITD. The clinical features of prominent cranial involvement and impaired speech distinguish this "non-DYT1" early-onset ITD family from the typical DYT1 phenotype.

Localization of a gene for myoclonus-dystonia to chromosome 7q21-q31.

Essential myoclonus-dystonia is a neurological condition characterized by myoclonic and dystonic muscle contractions and the absence of other neurological signs or laboratory abnormalities; it is often responsive to alcohol. The disorder may be familial with apparent autosomal dominant inheritance. We report a large kindred with essential familial myoclonus-dystonia and map a locus for the disorder to a 28-cM region of chromosome 7q21-q31.

Exclusion of the DYT1 locus in familial torticollis.

Clinical-genetic studies of idiopathic torsion dystonia (ITD) indicate that the DYT1 gene on chromosome 9q34 is responsible for most childhood limb-onset disease. The genetic basis of adult-onset ITD is less well studied. In most multiplex adult-onset ITD families, dystonia is limited to the cervical, cranial, or brachial muscles; in a few rare families, dystonia also involves the legs and trunk. Previous linkage studies have excluded the DYT1 locus in these atypical families. We studied two large non-Jewish families with adult-onset ITD limited to the cervical and brachial muscles and excluded the DYT1-containing region. This study further restricts the role of DYT1 to childhood limb-onset ITD and suggests that other genes are responsible for focal adult-onset ITD.

Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families.

The DYT1 locus on chromosome 9q34 is responsible for most childhood limb-onset idiopathic torsion dystonia (ITD). Linkage to DYT1 has been excluded in families with adult-onset, and predominantly cranial-cervical, ITD. We mapped a locus (DYT6) associated with prominent cranial-cervical ITD in two large Mennonite families to chromosome 8. An identical haplotype spanning 40-cM segregates with ITD in these families, suggesting a shared mutation from the recent past.