Neurodevelopmental disorder in a patient with HMBS and SCN3A variants-A possibly blended phenotype further delineating autosomal recessive HMBS related disease.

Monoallelic pathogenic HMBS variants are a well-established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS-related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8-year-old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had no epilepsy but sleep electroencephalogram showed paroxysmal changes in the right hemisphere with secondary generalizations. Brain magnetic resonance imaging was unremarkable apart from a few small white matter hyperintensities. Exome sequencing (ES) initially prioritized a SCN3A c.3822G>A de novo variant whose sole causative role was eventually questioned as not fully compatible with symptoms. ES reanalysis revealed a homozygous c.674G>A HMBS variant. In the monoallelic form this variant is a known cause of AIP, whereas in trans with another HMBS pathogenic variant it was associated with the HMBS-related leukoencephalopathy in four individuals. Despite lack of signs/symptoms of porphyria, literature analysis suggested that HMBS c.674G>A likely contributed to the disease either as the sole cause or together with SCN3A c.3822G>A as a part of blended phenotype. Our report adds to the relatively small number of described cases of HMBS-related leukoencephalopathy and emphasizes that autosomal recessive form of HMBS disease can be present in the absence of porphyria symptoms.

[Pathogenetic basis of optic nerve atrophy in methanol poisoning]. / Patogeneticheskie osnovy razvitiya atrofii zritel'nogo nerva pri toksicheskom porazhenii metanolom.

Optic nerve atrophy is a pathomorphological consequence of diseases of the peripheral neuron of the visual pathway, manifested as atrophy of nerve fibers of varying severity. The toxic effect of methanol is mainly associated with formic acid and formaldehyde, which suppress the cytochrome system, inhibit oxidative phosphorylation, and thereby cause a deficiency of adenosine triphosphoric acid, to which brain and retinal tissues are especially susceptible. When formiate accumulates, tissue respiration is disrupted, leading to pronounced tissue hypoxia. As a result of such methanol metabolism, metabolic acidosis occurs. Tissue hypoxia develops in the first few hours as a result of the action of formic acid on the respiratory enzyme chain at the cytochrome oxidase level. Hypoxia and, as a consequence, a decrease in energy supply lead to a disruption of biological oxidation and the development of apoptosis in the optic nerve fibers. Understanding the process of optic nerve atrophy development at the pathogenetic level in methyl alcohol intoxication will help make a correct early diagnosis and prescribe timely treatment.

RERE deficiency causes retinal and optic nerve atrophy through degeneration of retinal cells.

BACKGROUND: The arginine-glutamic acid dipeptide repeats gene (RERE) encodes a nuclear receptor coregulator that modulates gene expression through its interaction with transcriptional machinery. In humans, RERE deficiency causes neurodevelopmental disorder with or without structural defects of the brain, eye, heart, and kidney (NEDBEH). Ophthalmological defects are seen in approximately one third of individuals with NEDBEH and in RERE-deficient mice which can serve as a useful animal model. RESULTS: In mice, RERE is expressed in a subset of retinal ganglion cells (RGC), the lens epithelium, and the ciliary body during the embryonic period. RERE expression expands into the outer nuclear layer and the inner nuclear layer during the postnatal period. RERE-deficient mice have retinal and optic nerve atrophy. We show that RERE deficiency causes progressive loss of retinal cells and apoptosis of retinal cells in the ganglion cell layer as early as E17.5. The number of RGCs is also reduced in RERE-deficient embryos and mice. CONCLUSIONS: We conclude that RERE is required to control the apoptosis of retinal cells in the developing retina, and that RERE deficiency results in the retina atrophy through degeneration of the retinal cells and optic nerve atrophy through the loss of RGCs.

Relationship between changes in retinal nerve fiber layer thickness measured by SD-OCT and changes in visual field parameters in birdshot chorioretinopathy.

PURPOSE: To describe the structure-function relationship in birdshot chorioretinopathy (BSCR) using visual field data and peri-papillary retinal nerve fiber thickness (RNFL). METHODS: A total of 21 patients (34 eyes) with BSCR were evaluated prospectively from 2014 to 2018 (IMAGE-EYE cohort). Functional tests included measurement of visual acuity and visual field (30-2 SITA standard). Anatomical tests included fluorescein angiography, indocyanine green angiography, and spectral domain optical coherence tomography. RESULTS: Most of the patients were female (57%) with a mean age of 62 ± 8 years. Mean follow-up was 2.3 ± 0.6 years. Structural examination results were significantly modified in contrast to functional test results, with a significant reduction in mean RNFL (2.49 µm, p < 0.01), temporal RNFL (- 1.68 µm; p = 0.03) and lower nasal RNFL (- 2.83 µm; p = 0.003). A significant linear relationship was found (p = 0.001) between the visual field deficit (mean deviation (MD)) and the Napierian logarithm of the mean RNFL thickness. CONCLUSION: We found a subtle structural deterioration of the optic nerve (RNFL) during the follow-up, but not of the visual field. The significant relationship between structural (RNFL thickness) and functional measures (mean deviation) also supports the idea that RNFL thickness measurements could be useful for the mid-term monitoring of BSCR patients.

[Modern treatment of different forms of optic nerve atrophy]. / Sovremennye sposoby terapii razlichnykh form atrofii zritel'nogo nerva.

Optic nerve atrophy (ONA) is one of the most common causes of blindness and low vision in the world. The disease occurs in 60-68% of cases. The causes of optic nerve atrophy are diverse: inflammatory and vascular diseases of the optic nerve and retina, glaucoma, atherosclerosis of the main vessels of head and neck, diseases of central nervous system, intoxication of various etiologies, as well as congenital and hereditary diseases. The literature review presents data on the diagnosis and classification of optic nerve atrophy, as well as on drug and non-drug treatment in combination with physiotherapy.

Neurofilament light chain as biomarker in idiopathic intracranial hypertension.

BACKGROUND: Damage of the optic nerve is the major complication of idiopathic intracranial hypertension. A biomarker indicative for optic nerve damage would help identifying high-risk patients requiring surgical procedures. Here, we studied the potential of cerebrospinal fluid neurofilament to predict idiopathic intracranial hypertension-induced optic nerve damage. METHODS: In two centers, serum and cerebrospinal fluid of 61 patients with clinically suspected idiopathic intracranial hypertension were prospectively collected. Neurofilament concentrations were measured and related to ophthalmological assessment. RESULTS: The average cerebrospinal fluid neurofilament concentration in patients with moderate and severe papilledema was increased compared to patients with minor and no papilledema (1755 ± 3507 pg/ml vs. 244 ± 102 pg/ml; p < 0.001). Cerebrospinal fluid neurofilament concentrations correlated with the maximal lumbar puncture opening pressure (r = 0.67, p < 0.001). In patients fulfilling the Friedman criteria for idiopathic intracranial hypertension with or without papilledema (n = 35), development of bilateral visual field defects and bilateral atrophy of the optic nerve were associated with increased average age-adjusted cerebrospinal fluid neurofilament concentrations. At last follow-up (n = 30), 8/13 of patients with increased, but only 3/17 with normal, cerebrospinal fluid neurofilament had developed bilateral visual field defects and/or bilateral optic nerve atrophy resulting in a sensitivity of 72.7% and a specificity of 73.7% of cerebrospinal fluid neurofilament to detect permanent optic nerve damage. CONCLUSIONS: Cerebrospinal fluid neurofilament is a putative biomarker for optical nerve damage in idiopathic intracranial hypertension.

An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.

Heterozygous loss-of-function mutations in the X-linked gene CASK are associated with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) and ophthalmological disorders including optic nerve atrophy (ONA) and optic nerve hypoplasia (ONH). Recently, we have demonstrated that CASK(+/-) mice display ONH with 100% penetrance but exhibit no change in retinal lamination or structure. It is not clear if CASK loss-of-function predominantly affects retinal ganglion cells, or if other retinal cells like photoreceptors are also involved. Here, we report a heterozygous missense mutation in the N-terminal calcium/calmodulin-dependent kinase (CaMK) domain of the CASK protein in which a highly conserved leucine is mutated to the cyclic amino acid proline. In silico analysis suggests that the mutation may produce destabilizing structural changes. Experimentally, we observe pronounced misfolding and insolubility of the CASKL209P protein. Interestingly, the remaining soluble mutant protein fails to interact with Mint1, which specifically binds to CASK's CaMK domain, suggesting a mechanism for the phenotypes observed with the CASKL209P mutation. In addition to microcephaly, cerebellar hypoplasia and delayed development, the subject with the L209P mutation also presented with bilateral retinal dystrophy and ONA. Electroretinography indicated that rod photoreceptors are the most prominently affected cells. Our data suggest that the CASK interactions mediated by the CaMK domain may play a crucial role in retinal function, and thus, in addition to ONH, individuals with mutations in the CASK gene may exhibit other retinal disorders, depending on the nature of mutation.

Telemedical assessment of optic nerve head and retina in patients after recent minor stroke or TIA.

The aim of the study is to telemedically assess the prevalence of simple optic nerve atrophy and retinal arteriolar anomalies in subjects who have had a minor stroke or TIA within 14 days, and to compare these results with an age-matched control group. By using a mobile examination unit, retinal photographs were taken with a 45° non-mydriatic colour fundus camera (KOWA NM-45, non-mydriatic-alpha) in patients who had suffered from a minor stroke or TIA within 14 days of the time of the examination. Retinal photographs were focused on the optic nerve head region. Pupils were not dilated. The documented medical history and the retinal images were stored on a server using browser independent web-based software running on PCs, tablets and smartphones. After completing the upload of the medical interview and the retinal images into the electronic patient chart, all retinal images were evaluated via telemedicine by an experienced senior consultant ophthalmologist. Age-matched normotensive, non-diabetic subjects (aged 40-89 years) who reported no systemic or ocular diseases were used as the control group. Both study groups were divided into five decades of life (40-49; 50-59; 60-69; 70-79; 80-89 years). We calculated the prevalences and the ratios of prevalences of optic nerve atrophy and retinal arteriolar anomalies between the stroke and the control group per decades of life. 139 minor stroke or TIA subjects (aged 40-89 years) and 1611 age-matched control subjects were examined. In the stroke group, we found significantly increased prevalences of optic nerve atrophy and retinal arteriolar anomalies throughout the 5th-8th decade of life when compared to age-matched controls. The prevalence of optic nerve atrophy in stroke subjects outranged the prevalence in the controls depending on age-class by a factor of 3-21. Simple optic nerve atrophy is frequent in patients who have suffered from an ischemic stroke or TIA, and it seems to indicate vascular damage, indicating the necessity for telemedically assisted assessment of the optic nerve.

Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy.

The CACNA1A gene encodes the transmembrane pore-forming alpha-1A subunit of the Cav 2.1 P/Q-type voltage-gated calcium channel. Several heterozygous mutations within this gene, including nonsense mutations, missense mutations, and expansion of cytosine-adenine-guanine repeats, are known to cause three allelic autosomal dominant conditions-episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. An association with epilepsy and CACNA1A mutations has also been described. However, the link with epileptic encephalopathies has emerged only recently. Here we describe two patients, sister and brother, with compound heterozygous mutations in CACNA1A. Exome sequencing detected biallelic mutations in CACNA1A: A missense mutation c.4315T>A (p.Trp1439Arg) in exon 27, and a seven base pair deletion c.472_478delGCCTTCC (p.Ala158Thrfs*6) in exon 3. Both patients were normal at birth, but developed daily recurrent seizures in early infancy with concomitant extreme muscular hypotonia, hypokinesia, and global developmental delay. The brain MRI images showed progressive cerebral, cerebellar, and optic nerve atrophy. At the age of 5, both patients were blind and bedridden with a profound developmental delay. The elder sister died at that age. Their parents and two siblings were heterozygotes for one of those pathogenic mutations and expressed a milder phenotype. Both of them have intellectual disability and in addition the mother has adult onset cerebellar ataxia with a slowly progressive cerebellar atrophy. Compound heterozygous mutations in the CACNA1A gene presumably cause early onset epileptic encephalopathy, and progressive cerebral, cerebellar and optic nerve atrophy with reduced lifespan. © 2016 Wiley Periodicals, Inc.

Quantitative comparison of disc rim color in optic nerve atrophy of compressive optic neuropathy and glaucomatous optic neuropathy.

PURPOSE: The purpose was to investigate an objective and quantitative method to estimate the redness of the optic disc neuroretinal rim, and to determine the usefulness of this method to differentiate compressive optic neuropathy (CON) from glaucomatous optic neuropathy (GON). METHODS: In our study there were 126 eyes: 40 with CON, 40 with normal tension glaucoma (NTG), and 46 normal eyes (NOR). Digital color fundus photographs were assessed for the redness of disc rim color using ImageJ software. We separately measured the intensity of red, green, and blue pixels from RGB images. Three disc color indices (DCIs), which indicate the redness intensity, were calculated through existing formulas. RESULTS: All three DCIs of CON were significantly smaller than those of NOR (P < 0.001). In addition, when compared with NTG, DCIs were also significantly smaller in CON (P < 0.05). A comparison of mild CON and mild NTG (mean deviation (MD) > -6 dB), in which the extent of retinal nerve fiber layer thinning is comparable, the DCIs of mild CON were significantly smaller than those of mild NTG (P < 0.05). In contrast, DCIs did not differ between moderate-to-severe stages of CON and NTG (MD ≤ -6 dB), though the retinal nerve fibers of CON were more severely damaged than those of NTG. To differentiate between mild CON and mild NTG, all AUROCs for the three DCIs were above 0.700. CONCLUSIONS: A quantitative and objective assessment of optic disc color was useful in differentiating early-stage CON from GON and NOR.

Ophthalmic findings in the KIF1A-associated neurological disorder (KAND).

PURPOSE: To define the ophthalmic manifestations in KIF1A-associated neurological disorder (KAND), a rare, progressive neurodegenerative disorder caused by pathogenic variants in the KIFA1 gene. DESIGN: Cross-sectional study. METHODS: Clinical ophthalmic examination and multimodal imaging were performed for 24 participants enrolled in the KIF1AOutcome measures, Assessments, Longitudinal And endpoints (KOALA) Study. Visual evoked potentials (VEP) were performed on select participants. RESULTS: The average central visual acuity in pediatric participants was 20/43 (logMAR 0.329, range 0.0-1.0), and 20/119 (logMAR 0.773, range 0.471-1.351) in adults. Ninety-five percent of participants examined had some degree of optic nerve atrophy detected by clinical examination and/or optical coherence tomography (OCT). Almost forty percent had strabismus. Color vision, visual fields and stereopsis were impaired in most participants who were able to participate in testing. VEP showed varying degrees of signal slowing and diffuseness. CONCLUSIONS: Optic nerve atrophy is the primary ocular finding in individuals with KAND and is present at higher prevalence than previously reported. The degree of the atrophy is likely dependent on the severity of the pathogenic variant and possibly the age of the patient. Adults had worse vision on average than children, suggesting possible decline in vision with age. Strabismus in this cohort was common. Visual evoked potentials showed findings consistent with optic neuropathy and visual dysfunction even in the absence of obvious structural changes on OCT. Families should be counseled regarding visual impairment in KAND patients, so as to obtain appropriate support and assistance to maximize safety, functionality, and learning.

Giant 20/20 Meningioma: The Diagnostic Value of Confrontation Visual Fields.

Meningiomas are benign tumors of the central nervous system (CNS) that usually result in compression to adjacent structures and rarely cause pathology on their own. Meningiomas can affect the visual pathways originating from perineural or optic nerve sheath meningioma (ONSM), sellar, or clinoid, to the frontal-temporal-parietal-occipital lobes. Frontal meningiomas have an indolent presentation with frequent behavioral changes (i.e., personality or emotional changes, visual hallucinations), but they rarely present with visual disturbances. We present a case of a giant frontal meningioma causing progressive visual field loss despite preserved visual acuity and no behavioral changes. We aim to highlight the diagnostic value of performing a detailed ophthalmologic evaluation with confrontation visual field (CVF) testing and interpretation in aiding the discovery and diagnosis of intracranial tumors.

Beyond Vision and Hearing: A Case Report of Wolfram Syndrome.

Wolfram syndrome (WFS) is an uncommon autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, diabetes insipidus, optic nerve degeneration, hearing impairment, and other abnormalities. Additionally, a portion of individuals experience neurological, endocrine, behavioral, and urinary tract disorders that make management more challenging. Here, we present a 22-year-old male who was diagnosed with type 1 diabetes at the age of 4 and received treatment with basal-bolus insulin therapy. He had blurring of vision and hearing loss at 13 years of age, and our evaluation revealed optic atrophy and sensorineural hearing loss. He had polydipsia and polyuria (intake/output of 5-6 L/day) despite a fairly controlled blood glucose level. Serum anti-diuretic hormone (ADH) was done, which confirmed the diagnosis of central diabetes insipidus. His sonogram and urinary flow studies revealed bilateral hydroureteronephrosis with reflux uropathy. We diagnosed him with neurogenic bladder disorder with detrusor sphincter dyssynergia. This patient had an early onset urological disorder with involvement of eyes and ears, with diabetes mellitus and diabetes insipidus, which satisfied the criteria of WFS. The genetic test confirmed the diagnosis. He is currently being managed with insulin and desmopressin.

Blinding Optic Neuropathy Associated With Carboplatin Therapy: A Case Report and Literature Review.

Various forms of cancer and chemotherapeutics are associated with optic neuropathy. Cisplatin is a platinum analogue chemotherapeutic commonly associated with ocular toxicity among many other serious adverse effects. Carboplatin is a more chemically stable platinum analogue that is generally better tolerated with a comparatively favorable side effect profile. There are very few reports of carboplatin precipitating optic neuropathy. This case report describes a rare occurrence of carboplatin-induced blinding optic neuropathy. We treated a patient receiving carboplatin for neuroendocrine bladder cancer who developed rapidly progressive bilateral optic neuropathy over the course of three days. Upon evaluation at our clinic, his visual acuity had declined to light perception only and 20/60 in his left and right eye, respectively. Carboplatin therapy was immediately held and steroids were initiated. Despite the intervention, the patient's visual deficits have not improved at the one-year follow-up. Although the mechanism by which carboplatin causes ocular toxicity remains speculative, arterial ischemia appears to be the likely mechanism given the irreversible nature of visual decline. As demonstrated by our patient's course, irreversible vision loss despite high-dose steroid intervention necessitates expeditious recognition and management of this rare adverse effect. ​​​​​.

A Pair of Siblings With Wolfram Syndrome: A Review of the Literature and Treatment Options.

Wolfram syndrome (WS) is a rare genetic disorder typically characterized by juvenile onset diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, and neurodegeneration. There would be a high index of clinical suspicion for WS when clinical manifestations of type 1 diabetes and optic atrophy present together. Genetic analysis is often required to confirm the diagnosis. We describe a pair of Chinese siblings diagnosed with WS at ages 20 and 24 years, respectively. DNA sequencing of the WFS1 gene which encodes for Wolframin ER Transmembrane Glycoprotein identified a heterozygous nonsense variant NM_006005.3: c.1999C>T p.(Gln667*) and a heterozygous missense variant c.2170C>T p.(Pro724Ser) in exon 8 of the gene for both siblings. There is no curative treatment for WS and management of this debilitating disease is aimed at treating individual clinical manifestations, slowing disease progression, and improving quality of life. Treatment with liraglutide, a glucagon-like-peptide-1 receptor agonist, and tauroursodeoxycholic acid was started for the younger sibling, the proband. There was reduction in insulin requirements and improvement in glycemic control. The other sibling was not offered liraglutide due to her complex treatment regimen for end-organ failure. Genetic testing is a valuable tool to detect WS early to allow precise and prompt diagnosis, thereby facilitating the coordinated care from a multidisciplinary team of clinicians.

Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human.

OBJECTIVE: GABAA receptor subunit gene (GABR) mutations are significant causes of epilepsy, including syndromic epilepsy. This report for the first time, describes intractable epilepsy and blindness due to optic atrophy in our patient, who has a microdeletion of the GABRA1 and GABRG2 genes. We then characterized the molecular phenotypes and determined patho-mechanisms underlying the genotype-phenotype correlations in a mouse model who is haploinsufficient for both genes (Gabra1+/-/Gabrg2+/- mouse). METHODS: Electroencephalography was conducted in both human and mice with the same gene loss. GABAA receptor expression was evaluated by biochemical and imaging approaches. Optic nerve atrophy was evaluated with fundus photography in human while electronic microscopy, visual evoked potential and electroretinography recordings were conducted in mice. RESULTS: The patient has bilateral optical nerve atrophy. Mice displayed spontaneous seizures, reduced electroretinography oscillatory potential and reduced GABAA receptor α1, ß2 and γ2 subunit expression in various brain regions. Electronic microscopy showed that mice also had optic nerve degeneration, as indicated by increased G-ratio, the ratio of the inner axonal diameter to the total outer diameter, suggesting impaired myelination of axons. More importantly, we identified that phenobarbital was the most effective anticonvulsant in mice and the patient's seizures were also controlled with phenobarbital after failing multiple anti-seizure drugs. CONCLUSIONS: This study is the first report of haploinsufficiency of two GABR epilepsy genes and visual impairment due to altered axonal myelination and resultant optic nerve atrophy. The study suggests the far-reaching impact of GABR mutations and the translational significance of animal models with the same etiology.

Pneumosinus Dilatans: A Myriad of Symptomology.

Pneumosinus dilatans is an abnormal expansion of the air-filled paranasal sinuses. Usually found incidentally on radiology, it does rarely present in the form of cosmetic, neurological, ocular or rhinological pathologies. We report a case of a young male with complaints of bilateral gradual vision loss, diagnosed as pneumosinus dilatans with optic nerve atrophy. He underwent bilateral optic nerve decompression. A review of all cases of pneumosinus dilatans, reported over the last 100 years in English literature is presented.

The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases.

Oxidative stress is mainly caused by intracellular reactive oxygen species (ROS) production, which is highly associated with normal physiological homeostasis and the pathogenesis of diseases, particularly ocular diseases. Autophagy is a self-clearance pathway that removes oxidized cellular components and regulates cellular ROS levels. ROS can modulate autophagy activity through transcriptional and posttranslational mechanisms. Autophagy further triggers transcription factor activation and degrades impaired organelles and proteins to eliminate excessive ROS in cells. Thus, autophagy may play an antioxidant role in protecting ocular cells from oxidative stress. Nevertheless, excessive autophagy may cause autophagic cell death. In this review, we summarize the mechanisms of interaction between ROS and autophagy and their roles in the pathogenesis of several ocular diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and optic nerve atrophy, which are major causes of blindness. The autophagy modulators used to treat ocular diseases are further discussed. The findings of the studies reviewed here might shed light on the development and use of autophagy modulators for the future treatment of ocular diseases.

Broadening the phenotype of LRRK1 mutations - Features of malignant osteopetrosis and optic nerve atrophy with intrafamilial variable expressivity.

Osteosclerotic metaphyseal dysplasia is a rare disorder which features osteosclerosis involving long bones, vertebrae, ribs, clavicles and the iliac crests. Additional features which have variably been reported include developmental delay, short stature, hypotonia and seizures. The disease is caused by pathogenic variants in the LRRK1 gene, and inherited in an autosomal recessive manner. We report three siblings (ages 14 years, 11.5 years and 0.9 years), born to consanguineous parents of Arab-Muslim descent, harboring a homozygous pathogenic variant in the LRRK1 gene (Chr15:101068759 AGGGGCT>A, c.5965_5970del TGGGGC, p.Trp1989Gly1990del). The patients displayed variable degrees of skeletal dysplasia, with the oldest sibling most severely affected, and the youngest infant with minor skeletal involvement. Two of the siblings exhibited normal neurological development, while the youngest sibling exhibited global developmental delay. None of the siblings had seizures; however, two of them exhibited nystagmus. Optic nerve involvement has not previously been reported to be part of the clinical spectrum of this disease. The degree of optic nerve involvement did not correlate with the degree of skeletal involvement. This indicates both intra-familial variable expressivity along with a broadening of the spectrum of LRRK1-associated disease. These findings warrant reconsideration of therapeutic strategies, including the possibility of hematopoietic stem cell transplantation (HSCT) as is performed in cases of malignant and intermediate forms of osteopetrosis.

A novel homozygous variant in the SPG7 gene presenting with childhood optic nerve atrophy.

PURPOSE: To describe a case of hereditary spastic ataxia (HSP) presenting with childhood optic nerve atrophy and report a novel homozygous variant in the SPG7 gene. OBSERVATIONS: A 57-year-old man suffering from progressive optic nerve atrophy since childhood eventually underwent genetic testing. A targeted whole exome gene sequencing panel for optic neuropathy identified a novel homozygous variant in the SPG7 gene, c.2T > G, p.(Met?), which likely abolished production of paraplegin, an inner mitochondrial membrane protein. Subsequent neurologic examination revealed subtle signs of spastic paraplegia and ataxia in keeping with the genetic diagnosis of SPG7. CONCLUSION AND IMPORTANCE: Spastic paraplegia 7 (SPG7) is an autosomal recessive form of the neurodegenerative disorder HSP. Pure HSP is characterized by spastic paraparesis in the lower limbs, whereas complicated HSP presents additional neurological manifestations. This case report adds to the evidence that SPG7 can present with childhood optic nerve atrophy, preceding the characteristic SPG7 manifestations. SPG7 should be considered in the workup of suspected hereditary optic neuropathy.