Oscar F. Chacon-Camacho

Review and update on the molecular basis of Leber congenital amaurosis

Inherited retinal diseases are uncommon pathologies and one of the most harmful causes of childhood and adult blindness. Leber congenital amaurosis (LCA) is the most severe kind of these diseases accounting for approximately 5% of the whole retinal dystrophies and 20% of the children that study on blind schools. Clinical ophthalmologic findings including severe vision loss, nystagmus and ERG abnormalities should be suspected through the first year of life in this group of patients. Phenotypic variability is found when LCA patients have a full ophthalmologic examination. However, a correct diagnosis may be carried out; the determination of ophthalmologic clues as light sensibility, night blindness, fundus pigmentation, among other, join with electroretinographics findings, optical coherence tomography, and new technologies as molecular gene testing may help to reach to a precise diagnosis. Several retinal clinical features in LCA may suggest a genetic or gene particular defect; thus genetic-molecular tools could directly corroborate the clinical diagnosis. Currently, approximately 20 genes have been associated to LCA. In this review, historical perspective, clinical ophthalmological findings, new molecular-genetics technologies, possible phenotype-genotypes correlations, and gene therapy for some LCA genes are described.

ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation

The aim of this study was to assess the mutational spectrum of the ABCA4 gene in a cohort of patients with Stargardt disease from Mexico, a previously uncharacterized population. Clinical diagnosis in each patient was supported by a complete ophthalmological assessment that included visual acuity measurement, a slit lamp examination, a fundus examination and photography, electroretinography, fluorescein angiography, and computerized visual fields testing. Molecular analysis was performed by PCR amplification and direct nucleotide sequence of the 50 exons of the ABCA4 gene in genomic DNA. A total of 31 unrelated subjects with the disease were enrolled in the study. Molecular analysis in the total group of 62 alleles allowed the identification of 46 mutant ABCA4 alleles carrying 29 different pathogenic disease-associated mutations. Two ABCA4 mutant alleles were detected in 20 of the 31 patients (64.5%), a single disease allele was identified in six (19.4%), and no mutant alleles were detected in five of the cases (16.1%). Most patients with two ABCA4 mutations (11/20, 55%) were compound heterozygotes. Twelve variants were novel ABCA4 mutations. Nucleotide substitutions were the most frequent type of variation, occurring in 26 out of 29 (89.7%) different mutations. The two most common mutations in our study were the missense changes p.A1773V and p.G818E, which were identified in eight (17%) and seven (15%) of the total 46 disease-associated alleles, respectively. Haplotype analyses of intragenic SNPs in four subjects carrying the p.A1773V mutation supported a common origin for this mutation. In conclusion, this is the first report of ABCA4 molecular screening in Latin American Stargardt disease patients. Our results expand the mutational spectrum of the disease by adding 12 novel ABCA4 pathogenic variants and support the occurrence of a founder effect for the p.A1773V mutation in the Mexican population. The identification of recurrent mutations in our cohort will direct future ABCA4 molecular screening in patients from this ethnic group.

Congenital Hereditary Endothelial Dystrophy Caused by SLC4A11 Mutations Progresses to Harboyan Syndrome

Purpose: Homozygous mutations in SLC4A11 cause 2 rare recessive conditions: congenital hereditary endothelial dystrophy (CHED), affecting the cornea alone, and Harboyan syndrome consisting of corneal dystrophy and sensorineural hearing loss. In addition, adult-onset Fuchs endothelial corneal dystrophy (FECD) is associated with dominant mutations in SLC4A11. In this report, we investigate whether patients with CHED go on to develop hearing loss and whether their parents, who are carriers of an SLC4A11 mutation, show signs of having FECD. Methods: Patients with CHED were screened for mutations in the SLC4A11 gene and underwent audiometric testing. The patients and their parents underwent a clinical examination and specular microscopy. Results: Molecular analyses confirmed SLC4A11 mutations in 4 affected individuals from 3 families. All the patients were found to have varying degrees of sensorineural hearing loss at a higher frequency range. Guttate lesions were seen in 2 of the 4 parents who were available for examination. Conclusions: Our observations suggest that CHED caused by homozygous SLC4A11 mutations progresses to Harboyan syndrome, but the severity of this may vary considerably. Patients with CHED should therefore be monitored for progressive hearing loss. We could not determine conclusively whether the parents of the patients with CHED were at increased risk of developing late-onset FECD.

Expanding the Phenotype of Gingival Fibromatosis-Mental Retardation-Hypertrichosis (Zimmermann-Laband) Syndrome

Zimmermann–Laband syndrome (ZLS) is a rare disorder characterized by gingival fibromatosis, hypertrichosis, intellectual disability, and absence and/or hypoplasia of the nails or terminal phalanges of the hands and feet. The syndromic features of ZLS are highly variable and can overlap with other entities featuring gingival fibrosis. This study describes a patient with ZLS with novel findings, including colpocephaly, hemivertebra, polydactyly, hyperpigmentation, and hemihyperplasia. Thus, the present report expands the phenotypic spectrum of this uncommon syndrome.

Nasopalpebral lipoma-coloboma syndrome: clinical, radiological, and histopathological description of a novel sporadic case.

Nasopalpebral lipoma‐coloboma syndrome is an extremely uncommon autosomal dominant condition characterized by congenital upper eyelid and nasopalpebral lipomas, colobomata of upper and lower eyelids, telecanthus, and maxillary hypoplasia. A few familial and sporadic cases of this malformation syndrome have been previously reported. Here, the clinical, radiological, and histopathological features of a sporadic Mexican patient with the nasopalpebral lipoma‐coloboma syndrome are described. To our knowledge, this is the first time that craniofacial 3D computed tomography imaging was used for a detailed assessment of the facial lipoma.

Klippel–Feil syndrome associated with situs inversus: Description of a new case and exclusion of GDF1, GDF3 and GDF6 as causal genes

OBJECTIVE Klippel-Feil syndrome is characterized by faulty segmentation of two or more cervical vertebrae and, in its most severe form, consists of massive cervical vertebral fusion, short neck, low posterior hairline, and limitation of head movement. Several cases associating Klippel-Feil syndrome with situs inversus totalis have been reported. In the present study, we describe the clinical features of a novel case of Klippel-Feil syndrome associated with situs inversus totalis and searched for mutations in GDF1, GDF3 and GDF6 genes, which were recently implicated in the development of skeletal and visceral anomalies. METHODS A case of Klippel-Feil syndrome associated with situs inversus totalis underwent a full clinical examination including X-ray of cervical spine and thorax, abdominal ultrasound, and computerized tomography scanning of thorax and abdomen. PCR amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of GDF1, GDF3, and GDF6 genes were performed in genomic DNA. RESULTS No molecular alterations were found in GDF1, GDF3 and GDF6 genes in this patient. CONCLUSION An additional patient associating Klippel-Feil syndrome and situs inversus totalis is reported. Mutations in GDF1, GDF3, and GDF6 genes were excluded as the cause of this unusual clinical association.

OCT findings in young asymptomatic subjects carrying familial BEST1 gene mutations

Purpose: Best disease is an autosomal dominant retinal degeneration characterized by the presence of yellow lesions in the macula causing decreased central visual acuity at later stages. Best disease is caused by heterozygous mutations in BEST1, a gene located at chromosome 11q13. In the present study, we describe the clinical and molecular analysis of two multigenerational families with Best disease and correlate the optical coherence tomography (OCT) findings in asymptomatic and symptomatic subjects carrying BEST1 mutations. Methods: Two Mexican families with 3 affected generations each were studied. Probands underwent full ophthalmologic examination including fundus examination, fluorescent angiography (FAG), and electro-oculogram (EOG). Fourier-domain 3D OCT was performed in a number of symptomatic and asymptomatic subjects from these two pedigrees. PCR amplification and automated nucleotide sequencing of the 11 exons of the BEST1 gene in genomic DNA were also performed. Results: Eighteen members of family 1 were molecularly tested. Seven subjects, including 4 young asymptomatic patients, carried a W24C heterozygous mutation in BEST1. OCT imaging in a 6-year-old asymptomatic patient carrying this mutation did not demonstrate retinal lesions. Fifteen subjects from family 2 were molecularly tested. Four patients, including 2 asymptomatic subjects, carried a heterozygous Q293K BEST1 mutation. OCT imaging in an asymptomatic 8-year-old individual with the Q293K mutation demonstrated bilateral subfoveal lesions and unilateral serous retinal detachment. Symptomatic patients showed severe retinal lesions by OCT. Conclusions: Our results add to the clinical, imaging, and molecular knowledge of Best disease and suggest that OCT can recognize retinal lesions in some asymptomatic carriers of BEST1 mutations as early as 8 years of age.

Expansion of the Clinical Ocular Spectrum of Wolfram Syndrome in a Family Carrying a Novel WFS1 Gene Deletion

Abstract Purpose: To present the results of the clinical and molecular analyses of a familial case of Wolfram Syndrome (WFS) associated with a novel ocular anomaly. Methods: Full ophthalmologic examination was performed in two WFS siblings. Visante OCT imaging was used for assessing anterior segment anomalies. Genetic analysis included PCR amplification and exon-by-exon nucleotide sequencing of the WFS1 gene. Results: Ocular anomalies in both affected siblings included congenital cataract, glaucoma, and optic atrophy. Interestingly, microspherophakia, a feature that has not been previously associated with WFS, was observed in both siblings. Genetic analysis disclosed a novel c.1525_1539 homozygous deletion in exon 8 of WFS1 in DNA from both affected patients. Conclusions: The recognition of microspherophakia in two siblings carrying a novel WFS1 mutation expands the clinical and molecular spectrum of Wolfram syndrome.

Clinical and Genetic Characteristics of Mexican Patients with Juvenile Presentation of Niemann-Pick Type C Disease

Niemann-Pick type C disease (NPC) is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348∗ and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.

Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico

Background:  von Hippel‐Lindau disease (VHL) is an uncommon autosomal dominant condition predisposing to the development of tumours in a variety of body organs and caused by germline mutations in VHL, a tumour suppressor gene located on 3p. Up to 60% of VHL patients show ocular involvement with retinal hemangioblastoma being the most common observed lesion. In this study, we describe the clinical and genetic characteristics of two familial and one apparently non‐familial case of VHL ascertained at our institution.