Multisystem disorder in late-onset chronic progressive external ophthalmoplegia.

INTRODUCTION: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial syndrome on a disease spectrum with Kearns-Sayre syndrome (KSS). Clinical presentation is variable and our experience suggested that phenotypic differences exist in CPEO with onset after age 20. METHODS: This descriptive study is a retrospective chart review of 40 patients with late-onset CPEO. Clinical features, laboratory and neurophysiology results were reviewed. RESULTS: Multisystem dysfunction was very common in this series. Gastrointestinal dysfunction was more common than expected (60%) as was migraine headache (40%). Clinical characteristics on the KSS disease spectrum were uncommon in this series with only 2.5% having pigmentary retinopathy, 5% with cardiac conduction abnormality, and 22.5% having endocrinopathy (most often thyroid dysfunction rather than diabetes). Neurophysiology abnormalities included length-dependent axonal polyneuropathy in 44% (sometimes subclinical) and myopathic EMG changes in 26%. Exposure to sources of acquired mitochondrial toxicity including cigarette use and hepatitis C infection were more common than expected in this series. DISCUSSION: Phenotype was different in this late-onset series compared with previous reports in CPEO patients. In this series of late-onset patients, multi-organ dysfunction was more common than previously reported in CPEO, and some classical mitochondrial manifestations, such as pigmentary retinopathy were rare. We suggest that acquired mitochondrial toxicity may have a role in the pathogenesis of adult-onset CPEO.

Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an acute anterior uveitis cohort.

PURPOSE: Acute anterior uveitis (AAU) is the most common form of uveitis and is thought to be autoimmune in nature. Recent studies have described genes that act as master controllers of autoimmunity. Protein tyrosine phosphatase type 22 (PTPN22) and Cytotoxic T lymphocyte antigen-4 (CTLA-4) are two of these genes, and single nucleotide polymorphisms (SNPs) in the genes encoding these molecules have been associated with several autoimmune diseases. In this study we have analyzed SNPs in PTPN22 and CTLA-4 in patients with AAU. METHODS: The functional protein tyrosine phosphatase type 22 (PTPN22) SNP (R620W rs2476601, 1858C/T), and two CTLA-4 SNPs (rs5742909, -318C/T and rs231775, 49A/G) were analyzed in 140 patients with AAU and 92 healthy controls by sequence-specific primer -polymerase chain reaction (SSP-PCR). Data was analyzed by chi(2) analysis and Fisher's exact test. RESULTS: There was no significant association between PTPN22 620W, CTLA-4 -318C/T, or CTLA-4 49A/G and AAU. Similarly, there was no association with the three SNPs when patients were classified by race or gender. Finally, there was no association with the presence of ankylosing spondylitis in the patient cohort. CONCLUSIONS: The data do not support an association between SNPs in PTPN22 and CTLA-4, genes regarded as genetic master switches of autoimmunity. This raises the issue of the etiology of AAU and the possibility that it should be regarded as an autoinflammatory rather than an autoimmune condition.

Contribution of vitreous cytology to final clinical diagnosis fifteen-year review of vitreous cytology specimens from one institution.

PURPOSE: To assess the contribution of vitreous cytologic evaluation to the diagnosis of clinically undiagnosed vitritis. DESIGN: Retrospective chart review and database study. PARTICIPANTS: Two hundred seventy-eight eyes of 255 patients who had diagnostic vitrectomies. METHODS: We performed a retrospective review of all patients who had vitreous cytology specimens between October 1990 and October 2005 at Vancouver General Hospital. We reviewed the patient charts to obtain the results of microbial and other laboratory testing and to determine the follow-up course. MAIN OUTCOME MEASURES: Categories of vitreous cytology specimen results and final clinical diagnosis in patients who had diagnostic vitrectomy specimens. RESULTS: We reviewed vitreous cytology results from diagnostic vitrectomies in 278 eyes of 255 patients. One patient had 3 diagnostic vitrectomies, 21 patients had 2 procedures, and 233 patients had a single procedure. We categorized the results of vitreous cytologic examination into 6 major categories: acute inflammation consistent with endophthalmitis (n = 33), primary intraocular lymphoma (PIOL; n = 14), granulomatous inflammation (n = 41), mixed chronic nonspecific inflammation (n = 76), hypocellular specimens (n = 50), and miscellaneous specimens (n = 64). We determined that cytologic diagnosis aided or confirmed a clinical diagnosis, or ruled out PIOL, in 126/228 (55.3%) specimens where patients were not lost to follow-up. CONCLUSIONS: Cytologic analysis of vitreous specimens in clinically undiagnosed vitritis is a useful procedure, particularly in the diagnosis of endophthalmitis and PIOL. It is also helpful in confirming granulomatous, nonspecific, and miscellaneous clinical diagnoses and in ruling out PIOL. In this series, it helped to suggest or confirm a diagnosis in the majority of our specimens.

A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease.

OBJECTIVE: Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS: Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS: As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION: This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.