The genetics of anophthalmia and microphthalmia Bardakjian, Tanya M; Schneider, Adele
Current opinion in ophthalmology,
2011-September, 2011-Sep, 2011-09-00, 20110901, Letnik:
22, Številka:
5
Journal Article
PURPOSE OF REVIEWTo summarize recent breakthroughs regarding the genes known to play a role in normal ocular development in humans and to elucidate the role mutations in these genes play in ...anophthalmia and microphthalmia.
RECENT FINDINGSThe main themes discussed within this article are the various documented genetic advances in identifying the various causes of anophthalmia and microphthalmia. In addition, the complex interplay of these genes during critical embryonic development will be addressed.
SUMMARYThe recent identification of many eye development genes has changed the ability to identify a cause of anophthalmia and microphthalmia in many individuals. Syndrome identification and the availability of genetic testing underscores the desirability of evaluation by a geneticist for all individuals with anophthalmia and microphthalmia in order to provide appropriate management, long-term guidance, and genetic counseling.
Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may ...also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human KV4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the KV4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.
A 30-year-old man who recently immigrated from Liberia was admitted to the neurology service for diffuse weakness. He reported 7 years of painless progressive weakness and atrophy. He noted that his ...legs began to get weak first, which manifested as difficulty keeping up with his peers while playing soccer. This progressively worsened until he had great difficulty walking and arising from a seated position. A few years after the onset of leg weakness, he developed arm weakness.
Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among ...adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of
neuropathy,
-related disease,
-ALS,
related progressive gait decline and spasticity, and
-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.
BMP4
loss-of-function mutations and deletions have been shown to be associated with ocular, digital, and brain anomalies, but due to the paucity of these reports, the full phenotypic spectrum of ...human
BMP4
mutations is not clear. We screened 133 patients with a variety of ocular disorders for
BMP4
coding region mutations or genomic deletions.
BMP4
deletions were detected in two patients: a patient affected with SHORT syndrome and a patient with anterior segment anomalies along with craniofacial dysmorphism and cognitive impairment. In addition to this, three intragenic
BMP4
mutations were identified. A patient with anophthalmia, microphthalmia with sclerocornea, right-sided diaphragmatic hernia, and hydrocephalus was found to have a c.592C>T (p.R198X) nonsense mutation in
BMP4
. A frameshift mutation, c.171dupC (p.E58RfsX17), was identified in two half-siblings with anophthalmia/microphthalmia, discordant developmental delay/postaxial polydactyly, and poor growth as well as their unaffected mother; one affected sibling carried an additional
BMP4
mutation in the second allele, c.362A>G (p.H121R). This is the first report indicating a role for
BMP4
in SHORT syndrome, Axenfeld–Rieger malformation, growth delay, macrocephaly, and diaphragmatic hernia. These results significantly expand the number of reported loss-of-function mutations, further support the critical role of
BMP4
in ocular development, and provide additional evidence of variable expression/non-penetrance of
BMP4
mutations.
BackgroundQalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated ...amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy.Recent FindingsWe predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits.Implications for PracticeAs new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.
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