Isabelle Russell-Eggitt

Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome.

Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits. The gene involved in Alström syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alström syndrome and the common diseases that characterize it.

Heterozygous mutations of OTX2 cause severe ocular malformations

Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.

Risk, causes, and outcomes of visual impairment after loss of vision in the non-amblyopic eye: a population-based study.

BACKGROUND Screening for amblyopia in early childhood is done in many countries to ensure that affected children are detected and treated within the critical period, and achieve a level of vision in their amblyopic eye that would be useful should they lose vision in their non-amblyopic eye later in life. We aimed to investigate the risk, causes, and outcomes of visual impairment attributable to loss of vision in the non-amblyopic eye. METHODS For 24 months from July, 1997, national surveillance was done to identify all individuals in the UK with unilateral amblyopia (acuity worse than 6/12) who had newly acquired vision loss in the non-amblyopic eye, resulting in acuity of worse than 6/12 or visual-field restriction precluding driving. Information about participants was obtained at presentation and 1 year later. Participants were categorised as having socially significant visual impairment, or visual impairment, severe visual impairment, or blindness, in accordance with WHO taxonomy. FINDINGS Of 370 eligible individuals, at presentation 104 (28%) had socially significant visual impairment, 180 (49%) visual impairment, and 86 (23%) severe visual impairment or blindness. The minimum risk of permanent visual impairment by age 95 years was 32.9 (95% CI 29.1-36.9) per 100,000 total population. The projected lifetime risk of vision loss for an individual with amblyopia was at least 1.2% (95% CI 1.1-1.4). Only 36 (35%) of 102 people previously in paid employment were able to continue. INTERPRETATION In the UK, where screening for amblyopia is under review, risk of serious vision loss affecting the non-amblyopic eye and its results are greater than that previously assumed. Thus, in addition to the benefits of improved vision in the amblyopic eye, treatment of amblyopia during childhood is a potentially valuable strategy to prevent incapacitating vision loss later in life.

Aetiology of congenital and paediatric cataract in an Australian population

Background/aim: Paediatric cataract is a major cause of childhood blindness. Several genes associated with congenital and paediatric cataracts have been identified. The aim was to determine the incidence of cataract in a population, the proportion of hereditary cataracts, the mode of inheritance, and the clinical presentation. Methods: The Royal Childrens Hospital and the Royal Victorian Eye and Ear Hospital have a referral base for almost all paediatric patients with cataracts in south eastern Australia. The database contains cases seen over the past 25 years. The medical histories of these patients were reviewed. Results: 421 patients with paediatric cataract were identified, which gives an estimated incidence of 2.2 per 10 000 births. Of the 342 affected individuals with a negative family history, 50% were diagnosed during the first year of life, and 56/342 (16%) were associated with a recognised systemic disease or syndrome. Unilateral cataract was identified in 178/342 (52%) of sporadic cases. 79 children (from 54 nuclear families) had a positive family history. Of these 54 families, 45 were recruited for clinical examination and DNA collection. Ten nuclear families were subsequently found to be related, resulting in four larger pedigrees. Thus, 39 families have been studied. The mode of inheritance was autosomal dominant in 30 families, X linked in four, autosomal recessive in two, and uncertain in three. In total, 178 affected family members were examined; of these 8% presented with unilateral cataracts and 43% were diagnosed within the first year of life. Conclusions: In the paediatric cataract population examined, approximately half of the patients were diagnosed in the first year of life. More than 18% had a positive family history of cataracts. Of patients with hereditary cataracts 8% presented with unilateral involvement. Identification of the genes that cause paediatric and congenital cataract should help clarify the aetiology of some sporadic and unilateral cataracts.

Is early surgery for congenital cataract a risk factor for glaucoma

Aims: To estimate the risk of aphakic glaucoma after lensectomy for congenital cataract and its association with surgery within the first month of life. Method: A retrospective case notes review was conducted of all patients who had lensectomy for congenital cataract during their first year of life at Great Ormond Street Hospital between 1994 and 1997. Patients with pre-existing glaucoma, anterior segment dysgenesis, and Lowe syndrome were excluded. The risk of aphakic glaucoma after surgery was estimated using Kaplan-Meier survival analysis. Results: 80 patients, undergoing 128 lensectomies were eligible. Of these, six patients (nine eyes) were lost to follow up. Based on eye count, the risk of glaucoma by 5 years after lensectomy was 15.6% (95% CI 10.2 to 23.4). Based on patient count, the 5 year risk of glaucoma in at least one eye following bilateral surgery was 25.1% (95% CI 15.1 to 40.0). The incidence of glaucoma remained at a constant level for the first 5 years after surgery. After early bilateral lensectomy, within the first month of life, the 5 year risk of glaucoma in at least one eye was 50% (95% CI 27.8 to 77.1) compared to 14.9% (95% CI 6.5 to 32.1) with surgery performed later (log rank test, p = 0.012). There was no significant difference (Kolmogorov-Smirnov test: unilateral lensectomy p = 0.587, bilateral lensectomy p = 0.369) in 5 year visual outcomes between eyes operated before and after 1 month of age. Conclusion: Bilateral lensectomy during the first month of life is associated with a higher risk of subsequent glaucoma than with surgery performed later. The reason for this is unclear but it may be prudent, in bilateral cases, to consider delaying surgery until the infant is 4 weeks old. As the incidence of glaucoma is similar for each year after surgery, long term glaucoma surveillance is mandatory.

The morphology and natural history of childhood cataracts.

The morphology of congenital cataract reflects a combination of the timing and nature of the cause, the anatomy of the lens including its capsule, its development, and changes that take place with time. Morphology may variably affect prognosis, give a clue to the etiology and the age of onset and, in an isolated case, sometimes suggest heritability. The spectrum of morphological variations is enormous and can be complex. A comprehensive approach is to classify the variations according to the area of the lens involved, and sub-dividing them by a detailed description of the shape and appearance. Each specific morphological type is then analyzed determining the etiology, visual prognosis, and management. The use of gene markers has allowed many of these variations to be identified and categorized. Cataracts in childhood can involve the whole lens, in which case they are called total, Morgagnian, or disk-like. They can affect only the center of the lens: lamellar, nuclear, oil droplet, cortical, or coronary. They can be anterior: anterior polar, anterior subcapsular, or anterior lenticonus. The posterior aspect of the lens can also be affected in different fashions: Mittendorfs dot, posterior lenticonus, posterior cortical cataracts, or posterior subcapsular. There are five more forms that must be described separately: punctuate lens opacities, sutural cataracts, coralliform or crystalline, wedge-shaped, and persistent hyperplastic primary vitreous.

Prediction of improved vision in the amblyopic eye after visual loss in the non-amblyopic eye

Amblyopia arises from abnormal visual experiences in early childhood. Improved function of the amblyopic eye after visual loss in the non-amblyopic eye could be a model for residual neural plasticity. We aimed to establish the likelihood of, and predictive factors for, this improvement in function. We identified 254 individuals aged 11 years or older with unilateral amblyopia who were visually impaired after loss of vision in their non-amblyopic eye but had no other disorder affecting their amblyopic eye. 25 (10%) of 254 people had improved visual acuity in their amblyopic eye. These findings suggest there is some plasticity in the visual system of a few visually mature individuals with amblyopia, which warrants further study. Children should remain the focus of detection and treatment.

Neonatal cataract: Aetiology, pathogenesis and management

We review the epidemiology, aetiology, pathogenetic mechanisms and clinical management of neonatal cataract. Visual development and the effects of visual deprivation in the infant with congenital cataract are discussed and related to the timing of surgery. Surgical techniques and the important operative and post-operative complications are discussed. We review post-operative management and compare the different techniques available for aphakic correction, and describe the VEP changes found in patients with monocular cataract.

Congenital hypopituitarism: clinical, molecular and neuroradiological correlates

Objective  Recent studies have suggested that mutations in genes encoding several hypothalamo–pituitary (H–P) transcription factors result in hypopituitarism [isolated GH deficiency (IGHD) and combined pituitary hormone deficiency (CPHD)], which may in turn be related to the neuroanatomy revealed by magnetic resonance (MR) imaging. Although studies have focused on patients with either optic nerve hypoplasia (ONH) or isolated hypopituitarism with normal optic nerves, few studies have compared the two groups. We aimed to relate the clinical phenotype of a large cohort (n = 170) of children with congenital hypopituitarism including septo‐optic dysplasia (SOD) attending a single centre to the neuroradiological and genetic findings.

Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1

Objectives To identify CRB1 mutations in a large cohort of patients with recessive retinal dystrophies and to document the retinal phenotype and visual prognosis. Design A hospital-based cross-sectional study of children and adults with recessive retinal dystrophies. Participants Three hundred and six patients with Leber congenital amaurosis (LCA), early-onset childhood retinal dystrophy or juvenile onset retinitis pigmentosa were recruited to the study and gave blood samples for molecular genetic analysis. Methods A detailed clinical examination was performed, including: logMAR visual acuity, refraction, Goldmann visual fields, slit-lamp biomicroscopy, fundus photography, autofluorescence imaging and optical coherence tomography. The results of electrophysiology testing were available in all patients. DNA was obtained for molecular genetic analysis. Initial screening for mutations was performed using the LCA chip. Patients who had one or more CRB1 mutations identified on the chip, and other patients whose phenotype suggested a CRB1 genotype, underwent direct sequencing. In addition, consanguineous families segregating recessive RP underwent a whole genome scan using Affymetrix gene chips, and affected family members showing linkage to the RP12 locus underwent sequencing of the CRB1 gene. Main outcome measures Identification of patients with mutations in CRB1 and detailed documentation of the clinical phenotype. Results Mutations in CRB1, including 17 novel mutations, were identified in 41 patients from 32 families. The authors identified both disease mutations in 34 patients from 26 families, and these patients underwent detailed phenotyping. Common phenotypic features included hypermetropic refractive error, nummular pigmentation at the level of the RPE and increased retinal thickness on optical coherence tomography. Most patients had a clinical and electrophysiological phenotype consistent with a diagnosis of LCA or rod–cone dystrophy, but three patients had electroretinogram evidence of cone–rod degeneration. A minority of patients developed peripheral retinal telangiectasia, which in some cases led to seclusio pupillae and angle-closure glaucoma. Conclusion Mutations in CRB1 are associated with a range of recessively inherited retinal dystrophies, including LCA, childhood- and juvenile-onset rod–cone and cone–rod dystrophies. Although the phenotype is usually severe, in milder cases there is a window of opportunity for therapeutic intervention in early childhood.