Polyarticular Arthritis and Spinal Muscular Atrophy in Acid Ceramidase Deficiency Hooi Ling Teoh, MBBS, FRACP,A, B Alexander Solyom, MD,C Edward H

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Polyarticular Arthritis and Spinal Muscular Atrophy in Acid Ceramidase Deficiency Hooi Ling Teoh, MBBS, FRACP,a, b Alexander Solyom, MD,c Edward H. Schuchman, PhD, MPh,d David Mowat, MBBS, FRACP,b, e Tony Roscioli, MBBS, FRACP, PhD,e, f, g Michelle Farrar, MBBS, FRACP, PhD, a,b Hugo Sampaio, MBBCh, MPhil, FRACPa,b

Survival of motor neuron 1–negative spinal muscular atrophy (SMA) is abstract heterogeneous and remains a diagnostic challenge. The clinical spectrum continues to expand and ∼33 genes have been identified to date. The present report describes a 9-year-old girl with novel clinical phenotype of a patient with polyarticular arthritis followed by symptoms of SMA Departments of aNeurology and eMedical Genetics, due to acid ceramidase deficiency. Whole exome sequencing identified Sydney Children’s Hospital, Sydney Australia; bDiscipline compound heterozygous pathogenic mutation in the N-acylsphingosine of Paediatrics, School of Women’s and Children’s Health, UNSW Medicine, The University of New South Wales, Sydney, amidohydrolase 1 gene. Functional assay with leukocyte acid ceramidase Australia; cClinical Research, Plexcera Therapeutics LLC, activity showed a decreased level in the proband confirming pathogenicity New York, New York; dDepartment of Genetic and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, of the mutations. Mutations of N-acylsphingosine amidohydrolase 1 are New York; fSt Vincent’s Clinical School, University of New known to separately cause Farber disease (arthritis, subcutaneous nodules, South Wales, Darlinghurst, Australia; and gKinghorn Centre for Clinical Genomics, Darlinghurst, New South Wales, and dysphonia) or SMA with progressive myoclonic epilepsy. The present Australia combined phenotype is novel, bringing together SMA with progressive Dr Teoh clinically examined and interviewed the myoclonic epilepsy and Farber disease and establishing a phenotypic patient, collected data of the patient, interpreted spectrum. Acid ceramidase deficiency is an important consideration in whole exome data, and drafted and wrote the patients presenting with polyarticular arthritis and motor neuron disease. manuscript; Drs Solyom and Schuchman analyzed the acid ceramidase data and critically revised the manuscript; Dr Mowat was involved in patient care and critically revised the manuscript; Dr Survival of motor neuron 1-negative laryngeal involvement. In severe Roscioli obtained research funding for genomic spinal muscular atrophy (SMA) cases, pulmonary, liver, spleen, and sequencing, developed genomic consent forms for patient enrollment, supervised the creation of remains a diagnostic challenge. One central nervous systems may become the bioinformatics pipeline for genomic analysis, of the known variants is SMA with involved, with survival less than age performed bioinformatics analysis, and critically progressive myoclonic epilepsy 2 years.5 The spectrum of phenotypes revised the manuscript; Dr Farrar provided clinical (SMAPME), caused by homozygous associated with Farber disease has and scientifi c direction for the manuscript, and missense mutations in the recently expanded to include mild drafted and reviewed the manuscript; Dr Sampaio clinically examined and interviewed the patient, and N-acylsphingosine amidohydrolase arthritis, subcutaneous nodules, drafted and wrote the manuscript; and all authors ASAH1 1–3 1 ( ) gene and deficiency of and dysphonia, with onset in late approved the fi nal manuscript as submitted. the enzyme acid ceramidase. This childhood and may be misdiagnosed DOI: 10.1542/peds.2016-1068 is allelic with the lysosomal storage as juvenile idiopathic arthritis. 6 Accepted for publication Jun 21, 2016 disorder Farber disease (Farber lipogranulomatosis). 4 In contrast, SMAPME is characterized Address correspondence to Hugo Sampaio, MBBCh, by childhood-onset progressive Department of Neurology, Sydney Children’s Classic Farber disease manifests muscle weakness and amyotrophy Hospital, High St, Randwick NSW 2031, Australia. E-mail: [email protected] within the first 2 years of life and the development of myoclonic and has a unique triad of clinical epilepsy. Although it may be expected PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). manifestations that include that Farber disease and SMAPME may (1) painful and progressively have phenotypic overlap, none of the deformed joints (arthritis/ previous reports of SMAPME have had To cite: Teoh HL, Solyom A, Schuchman EH, et al. contractures), (2) subcutaneous the classic features of Farber disease, Polyarticular Arthritis and Spinal Muscular Atrophy nodules (lipogranulomata), and nor has the natural history of patients in Acid Ceramidase Defi ciency. Pediatrics. 2016; 138(4):e20161068 (3) progressive hoarseness due to with Farber disease surviving beyond

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 138 , number 4 , October 2016 :e 20161068 CASE REPORT early childhood revealed prominent denervation. Deletions or mutations according to protocols approved by lower motor neuron disease. were not identified in survival of the Human Ethics Committees of We describe a novel phenotype motor neuron 1 by molecular testing. South Eastern Sydney Local Health in a young girl with compound Creatine kinase was normal. District (HREC/13/POWH/203) heterozygous mutations in ASAH1 Australia. Initially, etanercept-induced (25 causing acid ceramidase deficiency, mg/wk) toxic motor neuropathy The initial whole exome sequencing who presented with polyarticular was considered as the etiology of data analysis confirmed several arthritis followed by SMA. the lower motor neuron disorder. 7 hundred rare variants with an Etanercept was therefore ceased allele frequency of <1% in control databases. Only 2 genes had at least CLINICAL BACKGROUND AND METHODS and abatacept, a CTLA4-Ig, was commenced at 200 mg monthly, 2 rare variants within the coding The proband presented at the age of as the latter is not known to sequence when analyzed for a 3 years with joint stiffness, swelling, cause neurologic complications. potential compound heterozygous and pain associated with increasing Progressive weakness occurred model, ASAH1 and UBQLN1. functional limitation. There over 48 months, with severe neck Only the variants in ASAH1 had were no subcutaneous nodules. and shoulder involvement requiring consistent pathogenicity analyses, Corticosteroids were commenced soft collar stabilization of the neck. including an inframe insertion, for seronegative polyarticular The patient became unable to rise NM_004315.4(ASAH1):c.642_647dup, arthritis. Weakness commenced at from a chair or the ground, lift arms p.(Phe215_Lys216insAsnPhe), age 5 years with initial difficulty above her head, or flex her pelvis and a missense variant, rising from the floor after previously against gravity. Distal strength NM_004315.4(ASAH1):c.566A>T, normal developmental milestones. was relatively preserved. Bulbar p.(Asn189Ile), not previously Progressive proximal weakness and dysfunction emerged, characterized reported. The Asparagine is highly amyotrophy became evident over the by tongue fasciculations and atrophy, conserved across multiple species. next 12 months, and she was unable incoordinated swallow, and recurrent In silico tools overall supported to squat, jump, or hop. Trendelenburg aspiration pneumonia ( Fig 1C). pathogenicity with a PolyPhen2 score gait and positive Gowers maneuver This was accompanied by cognitive of 0.958 (probably damaging), a were present. Deep tendon reflexes decline, memory disturbance, and sorting intolerant from tolerant score were pathologically brisk and plantar hoarse voice. Neuropsychometric of 0.1 (tolerated), and a combined responses extensor bilaterally. assessment at age 7 years annotation dependent development Joint disease was well controlled demonstrated mild intellectual score of 23.1. The mutations were on a combination of etanercept and impairment. Notably, when the Sanger sequenced for confirmation methotrexate. interval between abatacept infusions and each parent was found to carry was increased, joint symptomatology one of the variants supporting Neurophysiological studies of worsened. Acute respiratory autosomal recessive inheritance with upper and lower limbs showed infection exacerbated by restrictive a compound heterozygous model. preservation of sensory responses respiratory failure resulted in death and decreases in compound motor Acid ceramidase level was carried at age 9 years despite maximal action potential amplitudes with out by using a leukocyte assay in noninvasive ventilatory support. relative preservation of conduction the laboratory of Professor Edward Myoclonic jerks, epileptic seizures, velocities. Electromyography Schuchman, at Mount Sinai, NY, and or subcutaneous nodules were not identified chronic and active showed significantly decreased levels observed at any time. denervation consistent with of acid ceramidase activity when motor neuropathy/neuronopathy. compared with that of the parents Brain MRI was normal. Spine MRI (Fig 1D). These levels correlated with GENOMIC AND ENZYME those previously seen in patients demonstrated progressive angulation INVESTIGATIONS of the odontoid process with no who were severely affected by evidence of cervical myelopathy ( Fig Whole exome sequencing was Farber disease tested by the same 1A); however, somatosensory evoked carried out at the University of laboratory. potentials of upper and lower limbs Washington Genome Center. Sanger were prolonged for height and age sequencing was performed to DISCUSSION (>2 SD). Muscle biopsy confirmed confirm the mutations in proband denervation ( Fig 1B). Lower limb and for segregation analysis in family SMA associated with myoclonic MRI showed fatty infiltration of members. These procedures were epilepsy was first reported in a muscles, also consistent with performed with informed consent consanguineous Turkish family in

Downloaded from www.aappublications.org/news by guest on September 25, 2021 e2 TEOH et al FIGURE 1 Clinical, radiologic, pathologic, and biochemical features in a patient presenting with polyarticular arthritis and SMA. A, T1 sagittal MRI of cervical spine. Arrow depicts angulation of the odontoid. B, Muscle biopsy of quadriceps (ATPase stain, magnifi cation ×100) showing abnormal grouping of small type 2 fi bers (dark blue fi bers) and hypertrophic type 1 fi bers (pale blue fi bers), indicative of denervation. C, Tongue atrophy at age 8 years. D, Acid ceramidase level in leukocytes of patient, mother, and father.

2002,2 with whole exome sequencing together SMAPME and Farber disease The former mechanism may explain subsequently identifying mutations and establishing a phenotypic our patient’s Farber phenotype and in ASAH1. 3 There have been <10 spectrum. Acid ceramidase deficiency partial response of her arthritis reports of SMAPME so far, with a should therefore be an important to anti–tumor necrosis factor α phenotypic spectrum also including consideration in patients presenting agents. Odontoid abnormalities are a myoclonic-absence seizures with with polyarticular arthritis and feature of other lysosomal disorders denervation and mild weakness 8; motor neuron disease. and may account for pyramidal however, no obvious clinical overlap signs. Separately, pathologic with Farber disease has been Idiopathic arthritis, toxic motor studies in SMAPME demonstrate observed in patients presenting neuropathy, and cervical myelopathy defects in anterior horn cell axonal with a moderate non-neurologic were considered in our patient before branching and dendrite formation Farber disease phenotype, despite establishing a molecular genetic without granulomas, 3 suggesting the biochemical pathway being the diagnosis and uniting the various proapoptotic or other mechanisms same. The patient reported here is clinical features. Acid ceramidase may be more important in the unique in that she presented with deficiency results in the accumulation pathophysiology of SMAPME. joint symptoms initially attributed to of sphingolipids that are seronegative polyarticular arthritis proinflammatory (lipogranulomas) A further suggestion that may explain and subsequent SMA, bringing and proapoptotic in various tissues. 5 the different clinical manifestations

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 138 , number 4 , October 2016 e3 may relate to the level of residual A number of therapeutic strategies, of next-generation sequencing enzyme activity. In vitro residual including hematopoietic stem combined with clinical phenotyping activity of acid ceramidase has been cell transplantation and enzyme in yielding a diagnosis in rare found to be typically <10% compared replacement therapy are being diseases, of relevance to the diagnostic with controls in severe Farber developed for Farber disease, approach in non-SMN SMA. disease, whereas patients with highlighting the need to define SMAPME have been shown to have the phenotypic spectrum of acid reduced enzymatic activity of 30% ceramidase deficiency. Although ACKNOWLEDGMENTS compared with controls. 3 Although there is promise in ameliorating We acknowledge Dr Christine Loo for based on a very small number of peripheral symptoms, challenges her contribution to the pathological cases, these observations have led remain with central nervous system images and explanation, Dr Ying Zhu to discussion of the possibility that delivery, critical to improving for the setup of the bioinformatics such a difference may be related to neurologic symptoms. 9 Here, we pipeline, and Dr Michael Buckley the symptoms of SMAPME being demonstrate a novel overlapping and the SEALS Genetics laboratory restricted to the central nervous phenotype of moderate Farber of NSW Health Pathology for system, with a less fulminant, albeit disease, subsequent SMA, with performing the Sanger sequencing. devastating, phenotype. However, no epilepsy, confirmed mutations this does not seem to provide an in ASAH1, and acid ceramidase explanation of why patients with deficiency. This report confirms ABBREVIATIONS moderate Farber disease who the importance of considering ASAH1: N-acylsphingosine ami- survive into adulthood do not acid ceramidase deficiency in dohydrolase 1 consequently develop anterior horn patients with features of SMA SMA: spinal muscular atrophy cell disease. 8 There have not yet been who remain undiagnosed and SMAPME: spinal muscular enough comprehensive studies to also in those patients presenting atrophy with allow robust genotype-phenotype with polyarticular arthritis and progressive myoclonic correlations to be made for Farber hoarseness. Further, the present epilepsy disease and SMAPME phenotypes. case demonstrates the utility

Copyright © 2016 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: This work was supported by funding from the Motor Neurone Diseases Research Institute of Australia grant in aid. Dr Teoh received scholarship support from the Thyne Reid Foundation. Dr Farrar received support from the Motor Neurone Diseases Research Institute of Australia Beryl Bayley MND Postdoctoral Fellowship. POTENTIAL CONFLICT OF INTEREST: Dr Solyom has collected a large cohort of patients with Farber disease and provided the background insight on acid ceramidase defi ciency phenotypes. He is currently an employee of Plexcera Therapeutics LLC, which is developing an enzyme replacement therapy for Farber disease. Dr Schuchman is a founding shareholder of Plexcera Therapeutics LLC. The other authors have indicated they have no potential confl icts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 25, 2021 Polyarticular Arthritis and Spinal Muscular Atrophy in Acid Ceramidase Deficiency Hooi Ling Teoh, Alexander Solyom, Edward H. Schuchman, David Mowat, Tony Roscioli, Michelle Farrar and Hugo Sampaio Pediatrics 2016;138; DOI: 10.1542/peds.2016-1068 originally published online September 20, 2016;

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