Large Caucasian Family Research Articles

Ornithine transcarbamylase deficiency: A diagnostic odyssey

Ornithine transcarbamylase deficiency: A diagnostic odyssey

X-Linked Idiopathic Infantile Nystagmus (XLIIN): Case Report and Review of Literature

Infantile nystagmus syndrome (INS) is one of the most common forms of nystagmus. It can occur in isolation or with other ocular anomalies. While nystagmus is usually sporadic, familial cases exist and are most commonly X-linked with incomplete penetrance and variable expressivity. There are over 45 mutations reported in the FRMD7 gene. This review describes the possible underlying mechanisms of infantile nystagmus syndrome, clinical characterization, and principles of management including behavioral, refractive, pharmacological, and surgical options as well as determines the genetic basis of INS in one large Caucasian family with a novel mutation in FRMD7. Newer generation optical coherence tomography (OCT) allows for accurate phenotypical characterization of genetic subtypes of INS. Further studies into identifying unknown genetic mutations involved in infantile nystagmus syndrome will allow for development of cellular and animal models to help classify INS and guide future therapies.

Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by paroxysms of dystonic, choreic, ballistic, or athetoid movements. Attacks usually commence during childhood or early adulthood, typically lasting a few seconds to a few minutes, and they can occur up to 100 times daily. Attacks usually respond to low-dose carbamazepine [1]. Mutations in PRRT2 have been identified as a cause of autosomal dominant PKD [2] and replicated in other studies [3-7]. It remains important to report the clinical characteristics of genetically defined families in order to fully describe the clinical syndrome, including the presence of additional associated features beyond the movement disorder. In a large Caucasian family with PKD (Fig. 1), a detailed neurological history and clinical examination were undertaken. Sanger sequencing of PRRT2 was performed. Three individuals have PKD alone, and three individuals have PKD and infantile convulsions (IC). Two individuals had isolated IC, whilst two other individuals had at least one adolescent seizure but no movement disorder. The age of onset for the movement disorder ranged between 3 and 30 years. Infantile convulsions occurred between the age of 6 and 12 months. In all cases, PKD attacks were choreic or dystonic in nature, lasting less than a minute, and responded well to carbamazepine. Attacks were provoked by sudden movements in all, with stress in II:10 and III:9. Four individuals were treated with low-dose carbamazepine and/or phenytoin for PKD/IC, which abolished symptoms of the movement disorder. Neurological examination was normal (Table 1). Fig. 1 Pedigree of Family 1. All individuals with symptoms of PKD, PKD and IC, or isolated IC were found to have a frameshift mutation in PRRT2 (c.649_650InsC p.P217fsX7) indicated by a plus symbol; individuals found not to have the mutation are indicated by ... Table 1 Clinical descriptions and genotyping results for family members Sanger sequencing of PRRT2 revealed the recognized pathogenic (c.649_650InsC p.P217fsX7) heterozygous mutation [2-7] in all eight clinically affected individuals as well as in three of the seven clinically unaffected individuals (Fig. 1). PRRT2 mutations are unlikely to be the cause of adolescent-onset seizures in this family, as individual III:12 did not carry the mutation. Non-penetrance was observed in three individuals. Migraine with aura, as classified using the International Headache Society diagnostic criteria [8], co-segregated in all but one individual with the p.P217fsX7 mutation, including in three individuals who do not have symptoms of IC/PKD, but was not observed in individuals who did not carry the p.P217fsX7 mutation. Visual aura (positive visual phenomena) was most frequently reported, other types of aura including expressive dysphasia, alexia and alien hand syndrome were also described. Migraine frequency ranged from twice a year to three times a month. Reported triggers included stress, sleep deprivation and exercise. Two individuals were treated with low-dose propranolol for several months, which reduced the frequency and severity of migraine attacks, but did not improve symptoms of the movement disorder. Previously reported linkage studies for this kindred (family 3, Spacey et al.) [9] generated LOD scores that were not significant for the analysis of PKD alone or PKD ± IC. We repeated linkage analysis using Merlin [10], assuming an autosomal dominant mode of inheritance with 80 % penetrance. LOD scores for the PRRT2 mutation and PKD/IC and the PRRT2 mutation and migraine with aura are 1.65 and 2.7, respectively. Several kindreds with hemiplegic migraine and PRRT2 mutations have recently been reported [11]. Migraine (with and without aura) is over-represented in individuals with PRRT2 mutations and clustering of migraine has been identified in small kindred’s harboring PRRT2 mutations [12] In this large family, migraine with aura segregates in a Mendelian fashion in nine of 10 individuals with the PRRT2 mutation, the remaining individual is still in adolescence and could still go onto develop migraine. Furthermore, it highlights that in some families, migraine with aura may be the predominant phenotype associated with PRRT2 mutations, which is important to bear in mind when determining whether a patient with PKD/IC has a positive family history, to enable appropriate genetic counseling and testing. The association of migraine with PRRT2 mutations raises the question of whether genetic variation in PRRT2 might play a role in susceptibility to ‘common’ migraine with aura.

Novel missense mutations in exon 15 of desmoglein-2: Role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy?

BackgroundThe diagnosis of arrhythmogenic right ventricular cardiomyopathy can be challenging. Disease-causing mutations in desmosomal genes have been identified. A novel diagnostic feature, loss of immunoreactivity for plakoglobin from the intercalated disks, recently was proposed.ObjectiveThe purpose of this study was to identify two novel mutations in the intracellular cadherin segment of desmoglein-2 (G812S and C813R in exon 15). Co-segregation of the G812S mutation with disease expression was established in a large Caucasian family. Endomyocardial biopsies of two individuals showed reduced plakoglobin signal at the intercalated disk.MethodsTo understand the pathologic changes occurring in the diseased myocardium, functional studies on three mutations in exon 15 of desmoglein-2 (G812C, G812S, C813R) were performed.ResultsLocalization studies failed to detect any differences in targeting or stability of the mutant proteins, suggesting that they act via a dominant negative mechanism. Binding assays were performed to probe for altered binding affinities toward other desmosomal proteins, such as plakoglobin and plakophilin-2. Although no differences were observed for the mutated proteins in comparison to wild-type desmoglein-2, binding to plakophilin-2 depended on the expression system (i.e., bacterial vs mammalian protein expression). In addition, abnormal migration of the C813R mutant protein was observed in gel electrophoresis.ConclusionLoss of plakoglobin immunoreactivity from the intercalated disks appears to be the endpoint of complex pathologic changes, and our functional data suggest that yet unknown posttranslational modifications of desmoglein-2 might be involved.

COL1A1andCOL2A1Genes and Myopia Susceptibility: Evidence of Association and Suggestive Linkage to theCOL2A1Locus

Collagen involvement in myopia development via scleral remodeling is well-known. Recently, COL1A1 and COL2A1 gene polymorphisms were reported to be associated with high-grade and common myopia, respectively. This study was conducted to investigate whether these collagen genes are associated and/or genetically linked with myopia in large Caucasian family datasets. High-grade myopia was defined as <or=-5.00 D. Two independent datasets comprising 146 (Duke) and 130 (Cardiff) families with high-grade myopia participated in the association study. Allelic discrimination assays were performed on tagging SNPs for COL1A1 and COL2A1. The pedigree disequilibrium test (PDT) and the association test in the presence of linkage (APL) were used for association analyses. Linkage analyses for COL2A1 locus markers were performed with the Fastlink and Merlin programs in conjunction with data obtained from our collaborative whole-genome linkage study (254 families). Significant association was identified between five SNPs (rs1034762, rs1635529, rs1793933, rs3803183, and rs17122571) of the COL2A1 locus and high-grade myopia (P < 0.045, minimum (min) P = 0.008) and with myopia status set at <or=-0.50 or -0.75 D (min P = 0.004) in the Duke dataset. The SNP rs1635529 also showed significant association in the Cardiff dataset (<or=-5.00 D, min P = 0.004; <or=-0.50 D, min P = 0.007). Linkage analyses showed suggestive linkage to the COL2A1 locus on 12q. No association was found between COL1A1 SNPs and any degree of myopia. The COL2A1 gene was associated with high-grade myopia in two independent Caucasian family datasets. COL1A1 gene polymorphisms were not associated with myopia in our dataset, indicating possible heterogeneity across different ethnicities.

Genomewide Linkage in a Large Caucasian Family Maps a New Locus for Intracranial Aneurysms to Chromosome 13q

Familial aggregation of intracranial aneurysms (IAs) indicates a genetic role in the pathogenesis of this disease. Despite a number of reported susceptibility loci, no disease-causing gene variants have been identified. In this study, we used a parametric genomewide linkage approach to search for new IA susceptibility loci in a large Caucasian family. The affection status of family members with clinical signs of IA was confirmed with medical records or through radiological or surgical examinations. All other relatives were screened using MR angiography. Genomewide linkage analysis was performed on 35 subjects using approximately 250 000 single nucleotide polymorphic markers. Ten individuals had an IA. Linkage analysis using a dominant model showed significant linkage to a 7-cM region in 13q14.12-21.1 with a maximum logarithm of odds score of 4.56. A new IA susceptibility locus on 13q was identified, adding to the number of IA loci already reported. Given that no coding variants have been reported to date, it is possible that alternative genetic variants such as regulatory elements or copy number variation are important in IA pathogenesis. We are proceeding with attempts to identify such variants in our locus.

Molecular genetics of human aldehyde dehydrogenase.

Four non-allelic genes, which encode four different aldehyde dehydrogenase (ALDH) isozymes, have been cloned and characterized at the present time. The coding nucleotide sequences, and organization of introns and exons of these genes have been elucidated. The ALDH1 gene encodes the major cytosolic ALDH1 existing in the liver and other tissues. The genetic deficiency of this isozyme was found at a low frequency (<< 10%) in both Caucasians and Orientals. The deficiency and alcohol sensitivity character are inherited together in one large Caucasian family examined. The ALDH1 gene contains two hormone response elements in its upstream 5' region. The ALDH2 gene encodes the major liver mitochondrial ALDH2 which has a very low Km for acetaldehyde. The atypical ALDH2(2) allele is common (about 30%) in Orientals; and subjects with ALDH2(2) allele, both homozygous and heterozygous status, lack ALDH activity. These individuals are alcohol sensitive and have a markedly reduced risk in developing alcoholism and alcoholic liver diseases. The ALDH3 gene produces a cytosolic ALDH3 isozyme existing in the stomach and liver carcinoma but hardly in normal liver. The ALDH3 locus is polymorphic in Orientals and presumably other populations. The ALDH5 gene, which is expressed in testes and liver, is highly polymorphic in both Caucasians and Orientals. The variation of these two loci may affect the development of alcohol-related problems.

Hb Winnipeg or alpha 2 75(EF4)Asp leads to Tyr beta 2 in a large Caucasian family living in Georgia, USA.

Hb Winnipeg or alpha 2 75(EF4)Asp leads to Tyr beta 2 in a large Caucasian family living in Georgia, USA.