Optic Nerve Involvement in Farber Lipogranulomatosis: Expanding the Phenotypic Spectrum

Farber lipogranulomatosis (Farber disease [FD], MIM 228000) is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of acid ceramidase (AC) and is linked to ASAH1 gene mutations. ASAH1 mutations can lead to severe reduction in AC activity that causes accumulation of ceramides in various body tissues including the retina. The onset of clinical manifestations usually occurs during infancy, and the severity depends on residual ceramidase activity. Classic clinical features of FD include painful joint swelling, progressive dysphonia, and subcutaneous nodules. We report 2 unrelated patients presenting with classic FD phenotype who shared the same homozygous pathogenic mutation in the ASAH1 gene and optic neuropathy, thereby expanding the FD phenotypic spectrum.

Clinical Correspondence Optic Nerve Involvement in Farber Lipogranulomatosis: Expanding the Phenotypic Spectrum Abdullah S. Alamri, MBBS, Daniah A. Alshowaeir, MBBS, Ali A. AlFaiz, PhD, Fatimah H. Al Mousawi, BSc, Adel A. Mahmoud, MBBS, Aqeela H. Alhashim, MBBS F arber lipogranulomatosis (Farber disease [FD], MIM 228000) is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of acid ceramidase (AC) and is linked to ASAH1 gene mutations. ASAH1 mutations can lead to severe reduction in AC activity that causes accumulation of ceramides in various body tissues including the retina. The onset of clinical manifestations usually occurs during infancy, and the severity depends on residual ceramidase activity. Classic clinical features of FD include painful joint swelling, progressive dysphonia, and subcutaneous nodules. We report 2 unrelated patients presenting with classic FD phenotype who shared the same homozygous pathogenic mutation in the ASAH1 gene and optic neuropathy, thereby expanding the FD phenotypic spectrum. The first patient was a 2 1/2-year-old boy born to a consanguineous marriage. At 3 months of age, the patient started to develop multiple painful subcutaneous nodules followed by progressive joint contractures. The patient presented with voice hoarseness and poor vision at the age of 9 months (Fig. 1). His muscle bulk and tone were reduced, and deep tendon reflexes were depressed. Ophthalmologic evaluation showed nystagmus and inability to fixate or follow objects. The pupils were round and regular but nonreactive to light. Slit-lamp examination showed inferior corneal stromal opacities. Funduscopic examination revealed pale atrophic discs and retinal pigment epithelial changes with grayish opacification of the macula. Brain MRI showed global cerebral atrophy with delayed myelination (Fig. 1). Visual evoked potential (VEP) testing showed profound optic pathway dysfunction bilat- Pediatric Neurology Department (ASA, AAM, AHA), National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia; Department of Pediatrics (ASA), College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; Neuroophthalmology Unit (DAA), Ophthalmology Department, King Saud University, Riyadh, Saudi Arabia; and Research Center (AAA, FHAM), King Fahad Medical City, Riyadh, Saudi Arabia. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Abdullah S. Alamri, MBBS, P.O. Box 6651, Dammam 34212, Kingdom of Saudi Arabia; E-mail: asaalamri@ iau.edu.sa. Alamri et al: J Neuro-Ophthalmol 2019; 39: 391-393 erally (Fig. 2A). Nerve conduction studies showed evidence of peripheral neuropathy with some demyelination. The second patient was a 4-year-old girl who presented at the age of 5 months with voice hoarseness, irritability, and hypotonia, followed by development of painful erythematous nodules and multiple joint contractures. She had generalized hypotonia, diminished deep tendon reflexes, multiple subcutaneous nodules, and joint contractures (Fig. 1). Ophthalmic examination showed that both eyes had central, sustained, and maintained vision with mild nystagmus. Both pupils were round, regular, and reactive. No relative afferent pupillary defect was present. Lids were within normal limits. The cornea showed inferior stromal opacities. The fundi were within normal limits with minimal optic disc pallor. VEP testing showed bilateral mild latency delay (Fig. 2B). Targeted analysis of the ASAH1 gene in both patients revealed a homozygous missense mutation that was predicted to result in amino acid substitution at c.338T.G (p. V97G). Segregation analysis revealed a parental heterozygous state in both families. ASAH1 protein is a heterodimer consisting of 1 alpha and 1 beta subunit. Amino acid V97 is located on the alpha subunit, a residue that is highly conserved among different species and localizes to a ligandbinding site (See Supplemental Digital Content, Figures 1 and 2, http://links.lww.com/WNO/A375, http://links.lww. com/WNO/A376). Ocular manifestations that have mostly been associated with FD include a retinal cherry-red spot and corneal opacification. Other findings include blindness, poor visual fixation, and nystagmus. Farber's first description of the disorder reported that one of the patients was blind; however, no detailed visual examination was provided (1). To the best of our knowledge, this is the first report of optic neuropathy in FD. Both patients had ASAH1 variant V97G, which was reported in 2 siblings with a phenotype similar to that in our patients, except for myoclonic epilepsy. However, fundus examination was not reported for these cases (2). Cherry-red spots and pigmentary retinal changes have been reported in some patients with FD (3). Our first patient showed some grayish macular opacities, but there was no definite cherry-red spot. However, in storage diseases, the cherry-red spot may become faint after ganglion 391 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A-C. Photographs of the first patient, showing joint swelling and deformities (A) and subcutaneous nodules over the skull (B) and spine (C). D. Axial view of fluid-attenuated inversion recovery MRI brain imaging in the first patient at the level of the basal ganglia showing cerebral atrophy, delayed myelination, and subcutaneous nodules over the skull. Photographs of the second patient showing subcutaneous nodules over the skull (E) and joint deformities (F). cell loss. Corneal opacities were seen in our patients and reported previously as nodular corneal deposits (4). The optic disc pallor and VEP changes seen in our patients could be due to direct or indirect injury to the optic nerve. The mechanisms by which AC deficiency leads to the development of FD phenotype are not clearly understood. It is believed that the widespread infiltration of lipid-laden macrophages into various organs plays a role in some symptoms observed in patients with FD. However, the link between the build-up of ceramide primarily in lysosomes and infiltration of macrophages is still unclear. In addition, ceramide has a role in the breakdown and formation of other sphingolipids. Many of these lipids, such as sphingomyelin and complex glycolipids, play important roles in cell membranes. Other sphingolipids, such as glucosylceramides and sulfatides, are essential for the formation and breakdown of myelin. Zarbin et al studied the light and electron microscopic findings in the eyes of a 35-month-old girl with FD (5,6). They reported numerous lamellar bodies in endothelial cells of the retina, ganglion cells, and glial cells of the optic nerve corresponding to zebra-like bodies, which are principally associated with ceramide accumulation. Clinically, this patient had cherry-red spot, and histopathologically, these retinal ganglion cells showed the greatest changes and were filled with lipid-like inclusions. The chromatographic data supported that these cells are distended with ceramide. Similar findings were reported in a mouse model of AC deficiency. Fabian et al demonstrated significant cellular storage bodies in the retina and optic nerve. There was significant astrocytosis around the optic nerves associated with demyelination (7). Therefore, it seems that the pathology of visual loss in FD is complex, with both retinal and optic nerve involvement. Although both carried the same genetic variation, the first patient had a devastating course that was correlated with a significant reduction in enzymatic activity (0.049 vs 392 0.597 nmol/mg/h in the second patient). This could explain the worse visual outcome in the first patient. Cases described in this report expand the spectrum of FD phenotype with the addition of clinical optic nerve involvement confirmed with VEP recording. They also demonstrate the variability of the FD phenotype and severity despite sharing the same genetic variation. FIG. 2. A. Flash VEP for the right and left eye, respectively, in the first patient, showing extinguished waveform indicating bilateral profound optic nerve pathway impairment. B. Pattern VEP of the right and left eye, respectively, in the second patient, showing bilateral mild optic pathway involvement. C. VEP of normal child. VEP, visual evoked potential. Alamri et al: J Neuro-Ophthalmol 2019; 39: 391-393 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence This variant has been found in 3 families from the same tribe in Saudi Arabia, and we believe it is a founder mutation. the second case. The authors also thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: A. S. Alamri and A. H. Alhashim; b. acquisition of data: A. S. Alamri, D. A. Alshowaeir, A. A. AlFaiz, F. H. Al Mousawi, and A. H. Alhashim; c. analysis and interpretation of data: A. S. Alamri, D. A. Alshowaeir, A. A. AlFaiz, and A. H. Alhashim. Category 2: a. drafting the manuscript: A. S. Alamri, D. A. Alshowaeir, A. A. AlFaiz, and A. H. Alhashim; b. revising it for intellectual content: D. A. Alshowaeir, A. A. Mahmoud, and A. H. Alhashim. Category 3: a. final approval of the completed manuscript: A. S. Alamri, D. A. Alshowaeir, A. A. AlFaiz, F. H. Al Mousawi, A. A. Mahmoud, and A. H. Alhashim. REFERENCES ACKNOWLEDGMENTS The authors thank the patients and their parents for their cooperation. The authors extend their thanks to Dr. Dustin Tetzl from ENZYVANT and Dr. Schuchman from Mount Sinai School of Medicine for the enzyme analysis, and Drs. Hamad AlZaidan and Amal AlSeraihy from King Faisal Specialist hospital for providing clinical information about Alamri et al: J Neuro-Ophthalmol 2019; 39: 391-393 1. Yu FPS, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. 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