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To study the structure of lens epithelial cells (LECs) in the anterior lens epithelium of presenile cataract and to further explore the possible reasons for presenile cataract development. The anterior lens capsules (aLCs) of patients with presenile cataracts and patients with ordinary age-related cataracts were obtained from routine cataract surgery, and the 5–5.5 mm circles of the central aLC were cut in half and prepared for transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The most obvious structural changes in the LECs observed in both cataract groups by TEM were uneven thickness of the anterior lens epithelium, vacuolated cytoplasm and elongated nuclei. SEM showed abnormal structural changes in the LECs, with swollen cells and spheres on the anterior lens epithelium observed in both groups and holes formed by the LECs stretching observed only in the presenile cataract patients. The degeneration of the anterior lens epithelium and the structural changes in the LECs were observed more prominently in presenile cataract patients. Abnormal and prominently affected structural features of LECs were observed in the presenile compared to age-related cataract patients by TEM and SEM. We suppose that ultrastructural pathological changes in the anterior lens epithelial cells are one of the important reasons for the development of presenile and age-related cataract.

Purpose. The purpose of this study is to investigate the clinical characteristics of presenile cataract and compare that to ten years ago in southern Taiwan. Methods. The subjects who received cataract surgeries aged 30 to 54 years were recruited in Kaohsiung Chang Gung Memorial Hospital during September 2015 and August 2016. Patients with uveitis or those who received combined cataract surgeries were excluded. Retrospective chart review was performed in this study. Results. A total number of 2439 cataract surgeries were performed, and 302 (12.38%) eyes were having presenile cataract. Mean age was 47.55 ± 5.64 years old, and mean axial length was 26.00 ± 2.89 mm. Among 302 presenile cataract eyes, the leading cause was high myopia (defined as mean axial length ≥ 26 mm, 47.02%), followed by diabetes mellitus (26.82%). In types of lens opacity analysis, 67.55% of the patients were nuclear sclerosis dominant. Compared to the previous study 10 years ago, the leading cause of presenile cataract changed from idiopathy to high myopia, whereas the lens opacity types changed from posterior subcapsular opacity dominant to nuclear sclerosis dominant. Conclusions. High myopia has become the most important clinical characteristic associated with presenile cataract in a myopia epidemic area, and the most common type of lens opacity was nuclear sclerosis. With the increasing prevalence of high myopia, we should pay more attention to the management of presenile cataracts in high myopes to avoid complications.

MYH9-related disease (MYH-RD) is a syndrome complex associated with macrothrombocytopenia and Dohle-like leukocyte inclusion bodies with a risk of developing nephropathy, sensorineural hearing loss, and presenile cataracts. MYH9-RD is associated with mild to moderate mucocutaneous bleeding, including epistaxis, easy bruising, and heavy menstrual bleeding. Usually, local measures alone, or in combination with antifibrinolytics and/or desmopressin, are sufficient to obtain hemostasis. Platelet transfusions may be needed in the setting of bleeding refractory to first-line measures. Due to the complex nature of the care, management of patients with MYH9-RD should be done under the supervision of a hemophilia treatment center.

ResumenObjetivoDeterminar si el consumo de tabaco, alcohol, la presencia de hipertensión (HTA) y la diabetes son factores de riesgo (FR) para el desarrollo de cataratas.MétodosSe realizó un estudio retrospectivo comparando 3 grupos de pacientes: 72 sujetos menores de 55 años intervenidos de cataratas (grupo de cataratas preseniles); 101 sujetos mayores de 55 años intervenidos de cataratas (grupo de cataratas seniles) y 42 mayores de 55 años sin opacidad cristaliniana (grupo sin catarata). Se comparó la presencia de los FR anteriormente nombrados en cada grupo de estudio.ResultadosAl comparar la distribución de los FR entre el grupo con cataratas preseniles y el grupo con cataratas seniles observamos una importante asociación entre el consumo de tabaco o alcohol o la presencia de HTA y el riesgo para desarrollar cataratas en edades tempranas (p

Background Congenital cataract (CC) is a congenital abnormality characterized by lens opacity present at birth and is associated with highly heterogeneous clinical manifestations. Lens-specific integral membrane protein (LIM2) gene expression is localized to tight junctional domains of different lens fiber membranes. To date, only four mutations in LIM2 have been reported to be associated with congenital or presenile cataracts. Due to the rarity of variants detected in the gene, there is limited progress in understanding the correlation between the genotype and phenotype of patients with mutations in LIM2. Methods A total of four Chinese families with CCs were recruited for this study, including three families inheriting in an autosomal dominant (AD) pattern and one sporadic case. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Bioinformatics analysis was performed to evaluate the pathogenicity of the candidate variants. Exon 4 of LIM2 was amplified by polymerase chain reaction and directly sequenced. All patients underwent full ocular examinations. This was an observational study to explore the genotype-phenotype relationships in the four families with a common candidate variant. Results Various ocular phenotypes were detected in these families, mainly including CCs, elongated axial length, and myopia-related fundus changes. The LIM2 gene mutation, p.Arg130Cys, was detected in all patients. This was further confirmed by Sanger sequencing. The proportion of probands with this mutation in our CCs database was 3.1% (4/130), which indicated that this mutation appears to be a frequent cause of cataracts in the Han Chinese population. This variation has been reported by other investigators before and was correlated with isolated cataracts. Conclusions This is the first study that reports various ocular phenotypes associated with the p.Arg130Cys mutation in the LIM2 gene, which indicated the phenotypic heterogeneity of this gene. LIM2 might not only function as an integral membrane protein in lens fiber cells but also be associated with the axial development of the eyeball. Functional studies of the LIM2 gene are important and should receive more attention.

La malattia MYH9-correlata è una rara sindrome genetica caratterizzata da piastrinopenia congenita associata al rischio di sviluppare, durante l’infanzia o l’età adulta, ipoacusia neurosensoriale, nefropatia e cataratta presenile ad andamento evolutivo. Furono inclusi in uno studio retrospettivo tutti i casi con sordità da severa a profonda arruolati consecutivamente nel Registro Italiano dei pazienti affetti da malattia MYH9-correlata. La popolazione esaminata coinvolse 147 pazienti Italiani con malattia MYH9-correlata: l’ipoacusia fu identificata nel 52% dei casi e solo 4 pazienti (6%) presentarono un quadro di sordità da severa a profonda all’età media di 33 anni. In tutti i 4 pazienti, la sordità fu associata ad un lieve sanguinamento spontaneo e in 3 pazienti fu accompagnata da un coinvolgimento renale. L’impianto cocleare fu eseguito in 3 casi, con beneficio, in assenza di complicanze maggiori. La diagnosi di malattia MYH9-correlata fu eseguita circa 28 anni dopo la prima manifestazione clinica della malattia che non fu mai sospettata da un otorinolaringoiatra. Saranno discussi gli aspetti clinici e diagnostici di 4 pazienti con sordità da severa a profonda affetti da malattia MYH)-correlata, focalizzando anche le implicazioni terapeutiche.

Stickler syndrome or hereditary progressive arthroophthalmopathy is a heterogeneous group of collagen tissue disorders, characterized by orofacial features, ophthalmological features (high myopia, vitreoretinal degeneration, retinal detachment, and presenile cataracts), hearing impairment, mild spondyloepiphyseal dysplasia, and/or early onset arthritis. Stickler syndrome type I (ocular form) is caused by mutation in the COL2A1 gene. Ptosis and uveitis are relatively rare ophthalmological manifestations of this syndrome. We report an Indian boy having 2710C>T mutation in COL2A1 gene demonstrating short stature, ptosis, and uveitis with Stickler syndrome.

Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.

Myosin heavy chain-9-related disorders (MYH9-RDs) are a group of autosomal-dominant disorders caused by mutations in the MYH9 gene. The features include congenital macrothrombocytopaenia, inclusion bodies in neutrophils and a variable risk of developing sensorineural deafness, progressive renal impairment and presenile cataracts. A 44-year-old Caucasian man was initially thought to have Alport's syndrome and thrombocytopaenia secondary to idiopathic thrombocytopaenic purpura (ITP). A detailed family history and genetic analysis revealed a diagnosis of MYH9-RD. This case highlights the implications of a delayed diagnosis and the ongoing challenges encountered during management of individuals with this condition.

Aniridia is a congenital panocular disorder caused by the mutations of the paired box gene-6 (PAX6). To investigate the clinical characterization and the underlying genetic defect in a Chinese family with aniridia and other ocular abnormalities, we recruited the family members who underwent ophthalmic examination. Two patients in this family, the proband and his affected son, both have bilateral aniridia, foveal hypoplasia and nystagmus. Moreover, the proband also had presenile cataracts, but his affected son did not show cataracts at the time of examination. Sequencing PAX6 revealed that a heterozygous duplication mutation c.95_105dup11, predicted to generate non-functional truncated protein at position Gly36 (p.G36X), was found in the affected individuals but not in any of the unaffected family members including the parents of the proband. Haplotype analysis showed that the proband and his affected son shared a common disease-related haplotype, which was arisen from the proband's unaffected father through crossing-over. In conclusion, we identified a novel de novo duplication mutation of PAX6 in the aniridia and other ocular abnormalities family. This mutation has occurred de novo on a paternal chromosome by direct duplication, which presumably results from replication slippage or unequal non-sister chromatids exchange during spermatogenesis.

This paper reviews the most common causes of thrombocytopenia in the newborn. It mentions few classification schemes that clearly characterize the most common causes, diagnosis and treatment approaches for neonatal thrombocytopenia. Particular attention is paid to inborn macrothrombocytopenia without congenital anomalies. They represent a rare group of diseases, often captured randomly or during routine examinations. An attention is paid on congenital macrothrombocytopenia variants with mutations in the MYH9 gene. If they are not associated with other disorders (deafness, presenile cataracts, nephritis or renal failure), they may be mistakenly diagnosed as the acquired immune thrombocytopenic purpura (ITP). This distinguishing is essential to avoid potentially harmful and unnecessary treatment. The listed case report points to a situation where a detection of the root causes of neonatal thrombocytopenia led to a review of misdiagnosed ITP in the mother. A platelet size evaluation by both an appropriate cell counter and blood film examination is useful for differentiating a heterogeneous group of rare inherited macrothrombocytopenias. A healthy twin supported autosomal dominant inheritance. The results of investigations of twins and mother confirmed the congenital/inherited macrothrombocytopenia from the group of MYH9-related diseases (Tab. 5, Fig. 2, Ref. 21).

Elevated galactose levels can be caused by several enzyme defects, one of which is galactokinase. Galactokinase deficiency cause congenital cataracts during infancy and presenile cataracts in the adult population. We have isolated the mouse cDNA for galactokinase, which shares extensive amino acid sequence homology, 88% identity, with a recently cloned human galactokinase. It is expressed in all tissues examined. In an interspecific backcross analysis galactokinase maps to the distal region of mouse chromosome 11, a region that is homologous to human chromosome 17q22-25. The availability of the mouse gene provides an opportunity to make a knockout model for galactokinase deficiency.

Galactokinase is an essential enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. We have cloned the human galactokinase cDNA, which maps to chromosome 17q24, and show that the isolated cDNA expresses galactokinase activity in bacteria and mammalian cells. We also describe two different mutations in this gene in unrelated families with galactokinase deficiency and cataracts. The availability of the cloned galactokinase gene provides an important reference to identify mutations in patients with galactokinase deficiency and cataracts.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency plays an important biochemical role in the metabolism of the lens. Controversies exist in the literature on the possible association between G-6-PD deficiency and the development of cataracts. The authors present ten patients, aged between infancy and 40 years of age, who were admitted for bilateral congenital or presenile cataracts. These patients had no ocular or systemic disease which might have caused their cataract. The only systemic finding they had was G-6-PD deficiency. Two other patients among the families described suffered from bilateral congenital or presenile cataracts with no G-6-PD deficiency. This deficiency state does not appear to play a role in the production of their cataracts.

Myosin heavy chain 9 (MYH9)-related platelet disorders belong to the group of inherited thrombocytopenias. The MYH9 gene encodes the nonmuscle myosin heavy chain IIA (NMMHC-IIA), a cytoskeletal contractile protein. Several mutations in the MYH9 gene lead to premature release of platelets from the bone marrow, macrothrombocytopenia, and cytoplasmic inclusion bodies within leukocytes. Four overlapping syndromes, known as May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian platelet syndrome, describe different clinical manifestations of MYH9 gene mutations. Macrothrombocytopenia is present in all affected individuals, whereas only some develop additional clinical manifestations such as renal failure, hearing loss, and presenile cataracts. The bleeding tendency is usually moderate, with menorrhagia and easy bruising being most frequent. The biggest risk for the individual is inappropriate treatment due to misdiagnosis of chronic autoimmune thrombocytopenia. To date, 31 mutations of the MYH9 gene leading to macrothrombocytopenia have been identified, of which the upstream mutations up to amino acid approximately 1400 are more likely associated with syndromic manifestations than the downstream mutations. This review provides a short history of MYH9-related disorders, summarizes the clinical and laboratory characteristics, describes a diagnostic algorithm, presents recent results of animal models, and discusses aspects of therapeutic management.

MYH9-related disease (MYH9RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. All patients present with congenital macrothrombocytopenia and inclusion bodies in neutrophils. Some of them can also develop sensorineural deafness, presenile cataracts, and/or progressive nephritis leading to end-stage renal failure. The spectrum of mutations so far identified is peculiar, consisting of mostly missense mutations. Others are nonsense and frameshift mutations, all localized in the COOH terminus of the protein, or in-frame deletions. We report a family with three affected members carrying a novel mutation, the first duplication (p.E1066_A1072dup), of MYH9. The mutation was localized within exon 24, where the presence of a 16 nucleotide repeat was likely to be responsible for unequal crossing-over. Of note, a deletion of the same amino acids 1066_1072 was also identified in another MHY9RD family. Since two of the four patients with the duplication or the deletion in exon 24 were affected with bilateral neonatal cataracts, we speculate that these mutations might correlate with the ocular defect, which is reported only in 16% of MYH9RD patients.

Aim: To report a case of cataract and retinal detachment following an electrical injury in an adult Nigerian male. C a se report: A 28-year-old man presented with a history of progressive and painless loss of vision in the right eye, three years after an electric shock injury. There was no history of mechanical trauma. Examination and investigations revealed a mature cataract and retinal detachment in the right eye. He subsequently had an uneventful cataract surgery with expected poor prognosis, secondary to the retinal detachment. Conclusion: This case highlights two ocular complications (one common and one uncommon) following an electrical injury. A high index of suspicion and awareness of the likelihood of these complications may increase diagnostic accuracy, especially in cases of presenile cataracts with no apparent cause. Keywords : electrical injury, presenile cataract, retinal detachment Nigerian Journal of Ophthalmology Vol. 16 (1) 2008: pp. 23-25

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA). All patients present from birth with macrothrombocytopenia, but in infancy or adult life, some of them develop sensorineural deafness, presenile cataracts, and/or progressive nephritis leading to end-stage renal failure. No consistent correlations have been identified between the 27 different MYH9 mutations identified so far and the variable clinical evolution of the disease.We have evaluated 108 consecutive MYH9- RD patients belonging to 50 unrelated pedigrees. The risk of noncongenital manifestations associated with different genotypes was estimated over time by event-free survival analysis.We demonstrated that all subjects with mutations in the motor domain of NMMHC-IIA present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. We also evaluated the clinical course of patients with mutations in the four most frequently affected residues of NMMHC-IIA (responsible for 70% of MYH9-RD cases).We concluded that mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures. These findings are relevant not only to patients’ clinical management but also to the elucidation of the pathogenesis of the disease. Fil: Pecci, Alessandro. Universita Degli Studi Di Pavia; Italia. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Panza, Emanuele. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. Universidad de Bologna; Italia Fil: Pujol Moix, Núria. Hospital de la Santa Creu i Sant Pau; España Fil: Klersy, Catherine. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Di Bari, Filomena. Telethon Institute of Genetics and Medicine; Italia Fil: Bozzi, Valeria. Universita Degli Studi Di Pavia; Italia. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Gresele, Paolo. Università di Perugia; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Lethagen, Stefan. Universidad de Copenhagen; Dinamarca. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Fabris, Fabrizio. Università di Padova; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Dufour, Carlo. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Granata, Antonio. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. Policlinico "Vittorio Emanuele"; Italia Fil: Doubek, Michael. University Hospital; República Checa Fil: Pecoraro, Carmine. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. ‘‘Santobono’’ Children’s Hospital; Italia Fil: Koivisto, Pasi A.. Tampere University Hospital; Finlandia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Iolascon, Achille. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. Università degli Studi di Napoli Federico II; Italia Fil: Alvisi, Patrizia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. Ospedale Maggiore Carlo Alberto Pizzardi; Italia Fil: Schwabe, Dirk. Goethe Universitat Frankfurt; Alemania Fil: De Candia, Erica. Università degli studi di Roma "La Sapienza"; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Rocca, Bianca. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. Università degli studi di Roma "La Sapienza"; Italia Fil: Russo, Umberto. Ospedale Luigi Sacco; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Ramenghi, Ugo. Università degli studi di Torino; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Noris, Patrizia. Universita Degli Studi Di Pavia; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia Fil: Seri, Marco. Universidad de Bologna; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia Fil: Balduini, Carlo L.. Universita Degli Studi Di Pavia; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia Fil: Savoia, Anna. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia. IRCCS Policlinico San Matteo Foundation. Italian Registry for MYH9-Related Disease; Italia

Objectives To evaluate the possible synergistic role of partial galactose metabolism defects, high lactase (LPH) genotype and lactose and galactose ingestion in presenile cataract formation. Design and methods 51 patients with idiopathic presenile cataracts and 172 healthy cataract-free subjects were genotyped to determine their galactose-1-phosphate uridyl transferase (GALT) and LPH status. Whole milk, skimmed milk and yoghurt consumption was recorded in 19 cataract patients and 172 controls by questionnaire. Results GALT mutations and whole milk consumption increased the risk of cataract formation in high LPH genotype group, but not in lactose intolerant subjects. Logistic regression analysis showed the synergistic effect of GALT and LPH mutations on cataract formation. Conclusions High lactase activity genotypes and mutations in galactose-1-phosphate uridyl transferase have a synergistic effect on presenile cataract formation.

Background: Impaired activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD) has been suggested as a risk factor in cataractogenesis. The aim of this study was to determine the G6PD activity level in 89 male subjects of Dalmatian origin with idiopathic presenile cataracts. Methods: G6PD activity was determined by a quantitative spectrophotometric method. Results: Of 89 males with presenile cataracts only one (1.1%) had G6PD deficiency. The G6PD deficiency prevalence rate among males with presenile cataracts is not significantly different ( p > 0.05) from the prevalence of G6PD deficiency in the general population of Dalmatia (0.75% among men). Interpretation: The results of this study suggest that G6PD deficiency does not represent a pathogenetic factor in presenile cataract, at least not in the population of the southern part of Croatia.

Background Cerebrotendinous xanthomatosis (CTX) is a rare but treatable neurodegenerative disorder caused by 27-sterol hydroxylase (CYP27) deficiency. Objective To describe clinical features and results of genetic analysis in a family with CTX. Design Case report. Setting University hospital. Subjects A 54-year-old woman with CTX, her family members, and 115 white control subjects. Main Outcome Measures Results of clinical evaluation and magnetic resonance imaging of the brain in the affected subject; results of mutation analysis of the CYP27 coding sequence in the patient, her parents, and the control subjects. Results The proband and her affected sibling had classic features of CTX, including presenile cataracts, tendon xanthomas, diarrhea, and a complex neurodegenerative disorder. They were somewhat atypical, however, because their cataracts were congenital, cognitive impairment had been noted in childhood, and the white matter involvement was more severe than usual. The proband was shown to be homozygous for CYP27 mutation R362C. Similar analysis of 115 control subjects identified 1 subject who was a heterozygous carrier for this same CYP27 mutation. Conclusions The prevalence of CTX due to CYP27 mutation R362C alone is approximately 1 per 50 000 among white individuals. Although the disorder is rare, this incidence is substantially greater than previously recognized. Greater awareness of CTX is important because specific treatment is available.

Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is caused by inactivating mutations of the NF2 tumour suppressor gene.1,2 Multiple central and peripheral nervous system tumours and ocular abnormalities are common in NF2; bilateral vestibular schwannomas are pathognomonic for the disease. Genotype-phenotype correlations are well established for NF2 associated tumours. In general, constitutional nonsense or frameshift NF2 mutations are associated with severe NF2 (that is, earlier onset of symptoms and more tumours), splice site mutations with variable disease severity, and missense mutations with mild disease. Genotype-phenotype correlations have not been reported for the non-tumour manifestations of NF2. The most common of these manifestations is presenile cataracts, which occur in about 60–80% of people with NF2.3–5 In animal models, lens fibre cells that are more differentiated express less Nf2 protein than the epithelial regions of the lens, suggesting that the Nf2 protein may play a role in lens epithelial cell migration or elongation.6 The purpose of this study was to determine if there were genotype-phenotype correlations for cataracts in NF2. The study was based on the United Kingdom NF2 registry in the Department of Medical Genetics, St Mary’s Hospital, Manchester. NF2 patients are ascertained by contacting neurosurgeons, otolaryngologists, neurologists, paediatricians, dermatologists, and geneticists throughout the United Kingdom, augmented in the North West Region by the Regional Cancer Registry. The study was subject to continuing ethics committee evaluation and patients consented to participation. Patients were screened for constitutional NF2 mutations using single strand conformational polymorphism analysis (SSCP) as previously described,7 and examined for cataracts using slitlamp biomicroscopy at the time of diagnosis of NF2. For this study, cataracts were defined as present or absent (that is, posterior subcapsular cataracts and cortical cataracts were aggregated). There were 255 people from 190 families (159 people with new …

• A family composed of 13 affected members in five generations (10 patients from four generations examined) had vitreal and ophthalmoscopic findings characteristic of autosomal dominant vitreoretinochoroidopathy, as described in two previous kindreds. Visual acuity was 20/25 or better in all but one patient. All affected individuals had vitreous liquefaction with or without peripheral vitreal condensations. Peripheral pigmentary changes and choroidal atrophy were characteristic. Six patients developed cataracts in their early 40s that required extraction. One patient had glaucoma, one developed a retinal detachment, and one had a spontaneous vitreous hemorrhage. Autosomal dominant vitreoretinochoroidopathy is a welldefined condition featuring presenile cataracts, vitreal degeneration, characteristic ophthalmoscopic findings, and good visual prognosis.

Autosomal dominant vitreoretinochoroidopathy is a newly described fundus dystrophy characterized by abnormal chorioretinal hypopigmentation and hyperpigmentation, usually lying between the vortex veins and the ora serrata for 360 degrees. In this zone, there are a discrete posterior boundary, preretinal punctate white opacities, retinal arteriolar narrowing and occlusion, and, in some cases, choroidal atrophy. Most affected family members have diffuse retinal vascular incompetence, cystoid macular edema, and presenile cataracts. The vitreous is characterized by fibrillar condensation and a moderate number of cells. Electroretinograms are normal in younger affected individuals and are only moderately abnormal in older ones. Preretinal neovascularization, present in the posterior pole, is progressive in the proband. There are no identifiable systemic or skeletal abnormalities, high myopia, optically empty vitreous, lattice degeneration, areas of white-without-pressure, retinal breaks, or retinal detachment; thus, previously described vitreoretinopathies can be excluded from diagnostic consideration. Progression of this diagnostic seems to be extremely slow in most family members.

• Cataracts developed in two young adults who were receiving prolonged antiepileptic treatment with phenobarbital sodium and phenytoin sodium. The known side effects of these drugs are serious and varied, and phenytoin is strongly implicated in the etiology of cataracts in human beings. Results of our research study on rats supported our view on the cataractogenic action of phenytoin.

Ninety-four consecutive patients admitted for elective cataract surgery were prospectively examined for erythrocyte galactokinase activity. The presumed etiology for the cataract was established by history and physical examination in 51 patients (21 were diabetic). The cataract was classified as idiopathic in 43 patients. Galactokinase activity was significantly lower in idiopathic vs. presumed (nondiabetic) etiology patients 50 years of age or younger (P less than 0.05) and in idiopathic cataract patients 50 years of age or younger vs. those older than 51 years of age (P = 0.0033). Three of the idiopathic cataract patients (6.9%) had galactokinase levels less than two standard deviations below the mean galactokinase level for age-matched patients with suspected (nondiabetic) etiology. Compared with the expected distribution for the heterozygote in the general population (0.2%), this was highly significant (P = 0.0001). Diminished galactokinase activity may increase the risk of developing presenile cataracts requiring surgery by the fourth decade.

Background The conventional treatment for anisometropia brought on by asymmetric cataracts in presenile patients with high myopia is still controversial. In this report, we evaluate treatment results by chart review. Materials and Methods We reviewed the records of four patients under the age of 55 with high myopia and anisometropia associated with asymmetric lens opacity between fellow eyes. A four-step procedure was followed to confirm anisometropia induced by different degrees of lens opacity between the eyes. The eye with poorer best-corrected visual acuity (BCVA) in each patient underwent phacoemulsification with implantation of an intraocular lens. Different methods were used for vision correction in the fellow eyes, depending on the patient's lifestyle. Results All eyes that underwent cataract surgery achieved a BCVA of at least 6/6. Contact lenses were fitted in the fellow eyes of two patients and laser in situ keratomileusis (LASIK) was performed in the other two patients. Except for one of the eyes that underwent LASIK, each of the fellow eyes had satisfactory vision after correction. Conclusion Improved postoperative visual acuity was obtained in myopic eyes with presenile cataracts. LASIK may not be suitable for correcting refractive errors in fellow high myopic eyes in the early stages of cataracts.

Familial iridoschisis is a rare ocular disease and is probably transmitted as an autosomal dominant trait. The underlying abnormalities are not understood. Family members should be screened for this “condition as well as for associated ocular abnormalities”, namely presenile cataracts and narrow anterior chamber angle.

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency in RBCs was found significantly more frequently in 210 male cataractous patients than in 672 control subjects of Sardinian origin. The frequency of the deficiency was increasingly higher in presenile cataracts. In the G6PD-deficient group, the incidence of cortical and total cataracts was also increased. It is suggested that decrease of the G6PD activity in the lens, which accompanies its deficiency in the erythrocyte, might play a role in the cataractogenesis of these patients. Moreover, G6PD deficiency should be added to other conditions, such as the galactosemic states and riboflavin deficiency, where cataracts represent a sensitive indicator of metabolic abnormalities of the RBC.

Red blood cell galactokinase activity was measured in 70 patients with cataracts to assess a possible correlation between galactokinase activity levels and risk of cataract development. Among all, 15 patients developed cataracts during the first year of life, 25 patients under the age of 50 and 30 later in life. No cases of total or partial galactokinase deficiency were found. These results, taken together with the absence of cataracts in 9 patients with partial galactokinase deficiency render less certain the cause and effect relationship between partial galactokinase deficiency and the appearance of cataracts.

Five hundred patients undergoing cataract surgery were prospectively examined, and 46 Caucasian patients were found to have strictly idiopathic cataracts severe enough to warrant surgery on or before age 55. In a masked fashion we determined the activity of galactokinase (GK) and galactose-1-phosphate uridyl transferase (GPUT) in these patients as well as on 53 age matched controls. With respect to GK no cataract patient had an enzyme level of less than 2 standard deviations below the control mean. However, 3 of 45 (6.7%) patients in the cataract group had a GPUT level less than 2 standard deviations below the mean for controls, and were presumably heterozygotes for this enzyme. In comparison with the expected population rate of 0.8% this is highly significant (p = 0.006). Abnormalities in galactose pathway enzymes may therefore predispose to development of presenile cataracts. In affected people there is a possibility of treating these patients clinically by dietary restriction of dairy products or by using aldose reductase inhibitors to prevent or reverse cataract formation.

The activity of red blood cells galactose-1-P-uridyl transferase in 64 patients with presenile and senile cataracts (nondiabetics) and in 41 age-matched controls was investigated. All control subjects examined have shown normal enzymatic levels, while 21.9% of patients with presenile cataracts and 21.7% of patients with senile cataracts presented a statistically significant reduced enzymatic activity (mean +/- 2 SD in controls).

Red cells and the lens of the eye are nonnucleated cells; moreover, they have metabolic similarities. Cataracts develop in childhood in homozygotes for galactosaemic abnormalities, which can be detected by biochemical measurements in red blood-cells. It has not been determined whether heterozygotes for these defects are at greater risk for cataract development later in life. Similarly, riboflavin deficiency for which the erythrocyte is a sensitive indicator, has been associated with cataracts in animals. Red-cell studies were carried out in 22 patients, aged under 50, with cataracts. Heterozygosity for galactokinase deficiency was detected in 5 patients, for galactose-uridyl transferase in 2, and evidence of an erythrocytic deficiency of riboflavin in 8. Even when Black subjects were excluded from analysis because of their high incidence of polymorphism for galactokinase, these findings are significantly different from those expected from population surveys and suggest that many patients with presenile cataracts have a biochemical abnormality which can be detected by examination of red blood-cells and which may be corrected by dietary restrictions or supplements.

In Reply. —Our department is well aware of the possibility of galactose-1-phosphate uridyl transferase and galactokinase deficiency causing a presenile cataract. We have published a case report on the matter and we refer the author to this article.1 Blood drawn from both our patients showed normal levels of the above mentioned enzymes.

Based on our study of 32 affected individuals in 10 families, we suggest that the Wagner and the Stickler syndromes could be the same disorder. Both the Wagner and the Stickler syndromes are autosomal dominant disorders with a similar pattern of eye abnormalities, including myopia, presenile cataracts, strabismus, vitreo-retinal degeneration, retinal detachment and retino-schisis. Only the Stickler syndrome has been associated with non-ocular problems, such as cleft palate, micrognathia, mid facial hypoplasia, hearing loss and degenerative arthritis. All of the index cases in our study were ascertained because of their retinal symptoms as having the Wagner syndrome. Three families were included in a report on Wagner syndrome in Arch Ophthal. 89:176, 1973 by Hirose et al.