Luis H. Ospina

Mutations in C5ORF42 Cause Joubert Syndrome in the French Canadian Population

Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs*31], c.4804C>T [p.Arg1602*], and c.7477C>T [p.Arg2493*]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.

Mutations in TMEM231 cause Joubert syndrome in French Canadians

Background Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French–Canadian (FC) individuals. Methods and results Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42, known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231(c.12T>A[p.Tyr4*]; c.625G>A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors. Conclusions Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.

Treatment of Periocular Infantile Hemangiomas with Propranolol: Case Series of 18 Children

PURPOSE To study the efficacy of propranolol in the treatment of periocular infantile hemangiomas (IHs). DESIGN Retrospective interventional case series. PARTICIPANTS Eighteen children presenting periocular IH with occlusion of the pupil, anisometropic astigmatism, proliferating eyelid IH, or cosmetically disfiguring periocular IH. METHODS All patients received treatment with propranolol started at 0.5 mg/kg/day with an incremental increase by 0.5 mg/kg/day every 4 days, up to a maximum of 2 to 3 mg/kg/day. Complete eye examinations and serial photographs were obtained before, during, and after treatment. Doppler ultrasound and magnetic resonance imaging performed pre- and post-treatment were compared when available. MAIN OUTCOME MEASURES Evolution of the treated IH was evaluated with respect to astigmatism, amblyopia, and size of the lesion. RESULTS The IH size decreased in 17 of 18 patients. We noted a greater reduction when treatment was administered during the proliferative phase of growth of IHs. At the conclusion of treatment, none of our patients had amblyopia. The mean value of amblyogenic astigmatism (n = 7) decreased from 2.71 diopters (D) pretreatment to 1.03 D post-treatment. On radiology, 8 patients had significant regression of the lesion size of their IH and 1 patient had a limited progression. Propranolol had to be temporarily discontinued in only 1 patient because of symptomatic hypotension. CONCLUSIONS Propranolol seems to be an effective modality of treatment for periocular IH. It seems to be most efficacious when initiated in the proliferative phase of IH but may be beneficial even in the later stage. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

Visual acuity of children treated with chemotherapy for optic pathway gliomas

Chemotherapy is the most common primary treatment modality for pediatric optic pathway gliomas (OPGs). Due to the risk of severe visual impairment, visual acuity (VA) has become a clinical parameter of fundamental importance for children with OPGs. Despite this reality, most studies omit crucial information necessary for analysis of the effect of chemotherapy on VA in patients with cerebral gliomas. The principal goal of this study was to determine the immediate and long‐term visual outcome of children treated first with chemotherapy for OPGs.

Ocular neuromyotonia in a 15-year-old girl after radiation therapy.

A 15-year-old girl, previously treated with radiation, chemotherapy, and surgery for a posterior fossa medulloblastoma and parasellar metastasis at age 8, presented with a 10-month history of episodic horizontal diplopia. She was diagnosed with ocular neuromyotonia and successfully treated with oral carbamazepine. Given the strong association between peripheral neuromyotonia and the presence of autoimmune antivoltage-gated potassium channels, the patients blood was tested and found negative for these autoantibodies. This is the first time this has been verified in a person with ocular neuromyotonia.

Joubert Syndrome in French Canadians and Identification of Mutations in CEP104

Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.

Acquired myelinated nerve fibers in association with optic disk drusen

Myelinated retinal nerve fibers are a well-recognized anomaly of the ocular fundus associated with many ocular and systemic conditions. Myelination is almost always congenital and stable, but progression has been documented in rare cases. Optic disk drusen are the result of a degenerative process at the optic nerve head and are often found incidentally on ophthalmologic examination. To our knowledge, optic disk drusen have only been reported once in association with acquired and progressive myelinated retinal nerve fibers. We present 2 such cases and consider the implications for the pathogenesis of myelinated nerve fibers.

Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype

Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutations in a patient with a mild neurological phenotype and late-onset progressive visual impairment. MRI studies documented a progressive and selective involvement of the retrochiasmatic visual pathway. MTFMT was undetectable by immunoblot analysis of patient fibroblasts, resulting in specific defects in mitochondrial protein synthesis and assembly of the oxidative phosphorylation complexes. This report expands the clinical and MRI phenotypes associated with MTFMT mutations, illustrating the complexity of genotype-phenotype relationships in mitochondrial translation disorders.

Endophthalmitis Following Pediatric Cataract Surgery: An International Pediatric Ophthalmology and Strabismus Council Global Perspective

PURPOSE To compile international data on the risk factors, diagnosis, and treatment of endophthalmitis following pediatric cataract surgery. METHODS An e-mail containing a link to an online survey was sent to all members of the American Association for Pediatric Ophthalmology and Strabismus. The questionnaire examined the incidence, risk factors, treatment, outcomes, and prophylaxis of endophthalmitis following pediatric cataract surgery around the world. RESULTS Two hundred thirty-seven ophthalmologists answered the questionnaire. Eight ophthalmologists (3.4%) encountered 22 cases of endophthalmitis following pediatric cataract surgery during their practice. Most patients with endophthalmitis following pediatric cataract surgery were 2 to 4 years of age (36.4%). An intraocular lens was implanted in 59.1% of cases, most of which were acrylic intraocular lenses (53.8%). The main presenting symptoms were photophobia (50%) and pain (40.9%). The most common signs were conjunctival injection (36.4%) and hypopyon (31.8%). The final visual acuity was counting fingers or worse in 86% of cases. The most common cultured organism was Staphylococcus aureus (31.8%). The most common management of endophthalmitis following pediatric cataract surgery was a combination of intravitreal, systemic, and topical antibiotics (36.4%). Most ophthalmologists (68.2%) administered prophylactic intracameral antibiotic treatment during surgery and 50% used vancomycin. CONCLUSIONS Endophthalmitis following pediatric cataract surgery is an uncommon, multifactorial complication with poor visual prognosis. Efforts directed at minimizing its risk, such as treating potential predisposing systemic conditions, improving sterilization techniques, optimizing operative conditions to reduce complications and surgery duration, and using subconjunctival and intracameral antibiotics, decrease its incidence. Early postoperative evaluation, subsequent follow-up visits, and keeping a high index of suspicion should facilitate the recognition of endophthalmitis following pediatric cataract surgery to avoid delaying treatment. [J Pediatr Ophthalmol Strabismus. 2018;55(1):23-29.].