Kraoua I, Ben Younes T, Garcia V, Benrhouma H, Klaa H, Rouissi A, Levade T, Journal of Ben Youssef-Turki I. Farber disease: A Fatal Childhood Disorder with Nervous Rare Diseases Research System Involvement. J Rare Dis Res Treat. (2020) 5(3): 1-4 & Treatment www.rarediseasesjournal.com

Case Report Open Access

Farber disease: A Fatal Childhood Disorder with Nervous System Involvement Ichraf Kraoua1,2,3, Thouraya Ben Younes1,2,3*, Virginie Garcia4, Hanene Benrhouma1,2,3, Hedia Klaa1,2,3, Aida Rouissi1,2,3, Thierry Levade4,5, Ilhem Ben Youssef-Turki1,2,3 1Department of Child and Adolescent Neurology. National Institute Mongi Ben Hmida of Neurology. Tunis, Tunisia 2Research Laboratory LR18 SP04. National Institute Mongi Ben Hmida of Neurology. Tunis, Tunisia 3University of Tunis El Manar, Faculty of Medicine of Tunis. Tunis, Tunisia 4Cancer Research Center of Toulouse, INSERM UMR1037 and Université Paul Sabatier, Toulouse, France 5Laboratory of Metabolic Biochemistry, Federative Institute of Biology, CHU Purpan, Toulouse, France

Article Info ABSTRACT

Article Notes Farber Disease is an autosomal recessive inherited lysosomal storage Received: September 01, 2020 disorder which is characterized by tissue accumulation of . It is caused Accepted: Ocotber 06, 2020 by mutations within ASAH1 encoding for acid . It represents a rare *Correspondence: condition. Only twenty seven cases have been reported. Seven subtypes of Dr. Thouraya Ben Younes, Department of Child and Adolescent Farber disease have been identified. The clinical presentation is characterized Neurology. National Institute Mongi Ben Hmida of Neurology. by the appearance of subcutaneous skin nodules, bone and deformities, Tunis, Tunisia; Email: [email protected] and progressive hoarseness. Neurological symptoms as psychomotor delay or regression, hypotonia, seizures, and peripheral neuropathy were reported © 2020 Ben Younes T. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. in some subtypes of Farber disease. The nervous system involvement is correlated to poor prognosis. In this study, we report on clinical, biochemical Keywords: and molecular findings of two Tunisian siblings with Farber disease. Farber disease Lysosomal Ceramide ASAH1 Introduction Mutation Farber disease is a rare inborn lysosomal storage disorder Nervous system characterized by accumulation of ceramide (N-acylsphingosine) in 1. It is caused by mutations within ASAH12. It is associated with distinct clinical phenotypestissues, due to3 deficient activity of the acid ceramidase many cases 2 4. Herein, we report on . twoProgressive additional neurologic cases of Farberinvolvement disease was belonging reported to in a Tunisian family.. To date, twenty seven cases were reported Case report Patients are from consanguineous healthy parents from Tunisia during the period of 2015-2017. There was a family history of three maternal miscarriages, fulminant hepatopathy in a brother who

weightdied at wasthe age3.500 of kg10 (50 years.th - 85 Theth percentiles). first patient He was had a 22-month-oldnormal initial boy. He was born after an uneventful pregnancy and delivery. Birth sitting at the age of 6 months). At the age of 6 months, he presented psychomotor development (head control at the age of 2 months, nodules appeared. Later on, we noticed decreased oral intake and nowith gain hoarseness in motor skills. of the He was voice. referred Few monthsto our department later, subcutaneous at the age of 22 months. Examination at this age showed a normocephalic boy (50th -85th percentiles), a weight of 8.4 kg (below the 3rd percentiles),

fasciculations, nystagmus, hoarseness, and painful swelling of irritability, generalized hypotonia, brisk tendon reflexes, tongue

Page 1 of 4 Kraoua I, Ben Younes T, Garcia V, Benrhouma H, Klaa H, Rouissi A, Levade T, Ben Youssef-Turki I. Farber disease: A Fatal Childhood Disorder with Nervous Journal of Rare Diseases Research & Treatment System Involvement. J Rare Dis Res Treat. (2020) 5(3): 1-4

Hoffman sign, knee , and subcutaneous nodulesirritability, near hoarse the weakmetacarpal cry, brisk . tendon Taking reflexes, into bilateralaccount

tests (complete blood count, serum triglyceride and cholesterol,the family history, creatinine, Farber aspartate disease aminotransferase, was suspected. Biological alanine aminotransferase and creatine phosphokinase), brain MRI, EMG, electrocardiogram, fundus examination, and abdominal ultrasound were normal. Ceramidase enzyme

was treated symptomatically with analgesics. The patient activity assay and genetic study were not performed. She

showed a continuous worsening of her condition over the following months. Aged 20, she developed a cerebellar : subcutaneous skin nodules near interphalangeal, months after respiratory infection. Figure 1 syndrome and mystagmus. She died at the age of 2 years 6 metacarpal and wrist joints. Discussion Our study illustrates additional cases of Farber disease

1).the Fundus interphalangeal examination and showed metacarpal a bilateral joints. Thecherry-red fingers with nervous system involvement and fatal issue. were held flexed at the intraphalangeal joints (figure 5 The first case of Farber disease4 was described in 1957 spot. Biological tests disclosed to hypertriglyceridaemia byof Sidneylysosomal Farber acid . Itceramidase is a very rare which inherited is responsible disease. Ninety for (2.31mmol / l; normal values <1.7mmol / l), high level of 225 IU / L), and aspartate aminotransferase (51 IU / L; sixdegradation cases have of been ceramide reported into . It issphingosine caused by deficiencyand free lactate dehydrogenase (1578 IU / L; normal values: 100- fatty acids within lysosomes 6 normal values<35 IU / L). Alanine aminotransferase and 3. This condition results from mutations. Subsequently, in the ASAH1 there isgene an ofcreatine the corpus phosphokinase callosum and level diffuse were cortical normal and (13 subcortical IU / L; increased storage of ceramide in several organs and tissues normal values <45 IU / L). Brain MRI showed hypoplasia electromyography (EMG) were compatible with horn andThe is inherited pathogenesis in an ofautosomal Farber disease recessive is largely manner. unknown. cellatrophy. disease. The The results diagnosis of nerve of the conductionclassical form studies of Farber and Ceramide has been proposed to mediate apoptosis. Alterations of receptor-mediated apoptosis by ceramide peripheral leukocytes was found to be undetectable (0.05 disease was suspected. The activity of acid ceramidase on formation 3. The pathogenic mechanisms of accumulation in inflammatory cells may explain abnormal ASAH1 concluded to homozygosity for the Farber Disease were studied using acid ceramidase mutant nmol/h/mg; normal value: 9.8 nmol/h/mg). The gene mouse model generated by deletion of the acid ceramidase sequencingpresence of a of homozygous polymorphic change in exon 10 (c.737T>C,c.107A>G pathogenic p.Val246Ala). variation Our patient in exon showed 2 (p.Tyr36Cys) continuous and signal peptide sequence. It was shown that deletion of the signal peptide sequence disrupts lysosomal targeting and theworsening age of 3 of years his condition. 6 months. He developed at 3 years of age enzyme activity, resulting in ceramide and sphingomyelin7. seizures, respiratory and sleeping difficulties. He died at accumulation. Histiocytic infiltrations were observed in The second patient, the younger sister, who was already many tissues. The affected mice fail to thrive and die early born at the time of the diagnosis of Farber disease in her affectedSeven tissues.subtypes Type of Farber 1 represents disease have the beenclassical identified form pregnancy by cesarean section secondary to bicicatricial ofaccording the disease. to age It atincludes onset, severitypatients ofwith the subcutaneous disease, and uterus.brother, A was good 13 Apgarmonths score old. Shewas was recorded. born after Her an birth uneventful weight was 3 kg (15th - 50th psychomotor delay (head control at the age of 3 months, werenodules, reported. joint Type contractures, 2 and 3 patients and show voice only hoarseness. slight or percentiles). She had a moderate Progressive neurologic involvement and lung disease elbowssitting at extending the age of to 9 themonths, interphalangeal babbling at and 12 months).metacarpal At no symptoms of central nervous system disease. Type 4 is joints.the age Examinationof 9 months, sheshowed presented a head with circumference bilateral pain inof the45 associated with the “Neonatal-Visceral” variant. Neonates cm (15th -50th percentiles), a weight of 7.8 kg (3rd-15th andpresented seizures with beginning severe at organomegaly. 1 to 2 1/2 years Type of life. 5 Nodules patients percentiles), a length of 68 cm (below 3rd percentiles), manifested by progressive neurological deterioration

and joint involvement are less severe in this type. Type Page 2 of 4 Kraoua I, Ben Younes T, Garcia V, Benrhouma H, Klaa H, Rouissi A, Levade T, Ben Youssef-Turki I. Farber disease: A Fatal Childhood Disorder with Nervous Journal of Rare Diseases Research & Treatment System Involvement. J Rare Dis Res Treat. (2020) 5(3): 1-4

3. Our patients were treated symptomatically with analgesics. 6 is termed “Combined Farber and reversible variant.” Type 7 patients have reduced glucocerebrosidase,6, 8. galactocerebrosidase and ceramidase activities resulting The early-onset neurovisceral form of Farber disease fromOur patients were activator diagnosed prosaposin with type deficiency 1 Farber disease. described family, patients die at approximately 2 years of First symptoms usually appear at 3-6 months of age. They has a poor prognosis. As observed in the presently include deformed joints, painful subcutaneous nodules, 3. age because of nervous system involvement or respiratory 6 mptom of Farber disease in our patients was insufficiency,Conclusion as observed in our cases and progressive hoarseness due to laryngeal involvement . The first sy noted during the first year of life, as reported in litterature. whichFarber makes disease prognosis is a rare poor. and It must severe be inherited suspected disease. in the delayInvolvement or regression, of the peripheralseizures, nystagmus, and central hypotonia, nervous system ataxia, presenceIt could affect of psychomotorboth central andretardation peripheral or nervous psychomotor system lossis observed of central in some white subtypes matter, of or the peripheral disease. Psychomotor neuropathy regression, particularly in the presence of subcutaneous . Electromyogram shows sensory and motor demyelinating2, 8, 9 neuropathy or cell horn disease have2 been reported phenotypenodules and and hoarse to start voice. family Early screening. diagnosis Multidisciplinary helps prevent complications. Genetic diagnosis is necessary to confirm the delay. Both and patients regression. presented The with older central patient nervous had systemalso a with Farber disease. involvement represented essentially by psychomotor team involvement is crucial for the management of patients References examination showed cherry red spot in some cases as seen peripheral nervous system involvement. Ophthalmological 1. Paschke E, et al. Farber lipogranulomatosis type 1–late presentation 6, 9. Cvitanovic-Sojat L, Juraski R.G, Sabourdy F, Fensom A, Fumic ASAH1 K, in the first patient marker, normocytic anemia, hyperferritinaemia, and early death in a Croatian boy with a novel homozygous Some biological anomalies like increased inflammatory 2. mutation. Eur J Paediatr Neurol. 2011;15(2):171-173. ASAH1 mutation found in Farber disease Chedrawi AK, Al-Hassnan ZN, Al-Muhaizea M, Colak D, Al-Younes B, reportedhypertriglyceridaemia, 10, 11. The last elevatedthree anomalies aspartate were aminotransferase noted in the Albakheet A, et al. Novel V97G levels, and high level of lactate dehydrogenase were patients: unique appearance of the disease with an intermediate severity, and marked early involvement of central and peripheral 3. nervous system. Brain Dev. 2012;34(5):400-404. first patient. Ehlert K, Frosch M, Fehse N, Zander A, Roth J, Vormoor J. Farber The diagnosis of Farber disease is confirmed by disease: clinical presentation, pathogenesis and a new approach to 4. bydetermination demonstration of acid of ceramidasegranulomas activitywith macrophages measured in treatment. Pediatr Rheumatol. 2007;5:15. containingcultured skin lipid fibroblasts, cytoplasmic white inclusions blood cells in orsubcutaneous amniocytes, anZielonka ultra-orphan M, Garbade condition SF, Kölker with S,rheumatologic Hoffmann GF, and Ries neurological M. A cross- sectional quantitative analysis of the natural history of Farber disease: nodules, or by determination of ceramide accumulation in tissues by chromatography or mass spectrometry 3. The 5. cardinal disease features. Genet Med. 2018;20(5):524-530. Farber S, Cohen J, Uzman L. Lipogranulomatosis; a new lipo- 6. glycoprotein storage disease. J Mt Sinai Hosp N Y. 1957;24(6):816-37. activity of acid ceramidase on peripheral leukocytes was ASAH1 Al Jasmi F. A novel mutation in an atypical presentation of the rare found to be undetectable in our first patient. 7. infantile Farber disease. Brain Dev. 2012;34(6):533-535. A, et al. Pathological Manifestations of Farber Disease in a New Mouse foundA variety12. No ofclear mutations phenotype-genotype in the genecorrelation have been has Beckmann N, Kadow S, Schumacher F, Gothert JR, Kesper S, Draeger identified. About 8 sixty different mutations have been been established . Our patient was homoallelic for the 8. Model. Biol. Chem. 2018;399(10):1183-1202. p.Tyr36Cys substitution, which is reported to cause a rapid 13 Ehlert K, Levade T, Di Rocco M, Lanino E, Albert MH, Führer M, et al. degradation of the mature enzyme . This underlines Allogeneic hematopoietic cell transplantation in Farber disease. J the pathogenic role of this particular mutation in the Inherit Metab Dis 2019; 42(2):286-294.

9. 150.Cappellari AM, Torcoletti M, Triulzi F, Corona F. Nervous system involvement in Farber disease. J Inherit Metab Dis. 2016;39(1):149- development of a severe neurological phenotype. 10. Torcoletti M, Petaccia A, Pinto RM, Hladnik U, Locatelli F, Agostoni C, et It is focused on pain therapy, physical therapy and The management of Farber disease is mainly palliative. allogeneical. Farber diseasehaematopoietic in infancy stem resembling cell transplantation. juvenile idiopathic Rheumatology : transplantation has shown some promising results on identification of two new mutations and a good early response to surgical correction of joint contractures. Bone marrow 8 11. (Oxford). 2014;53(8):1533-1534. patients with minimal central nervous system involvement Nivaggioni V, Cano A, Arnoux I, Michel G, Loosveld M. Early . It may not be appropriate for patients with central nervous morphological diagnosis of Farber disease. Br J Haematol, system involvement as ceramide neurotoxicity may not be 2016;175(2):189.

Page 3 of 4 Kraoua I, Ben Younes T, Garcia V, Benrhouma H, Klaa H, Rouissi A, Levade T, Ben Youssef-Turki I. Farber disease: A Fatal Childhood Disorder with Nervous Journal of Rare Diseases Research & Treatment System Involvement. J Rare Dis Res Treat. (2020) 5(3): 1-4

12. 13.

Fabian P, Amintas S, Levade T, Medin JA. Acid ceramidase Bär J, Linke T, Ferlinz K, Neumann U, Schuchman EH, Sandhoff K. deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis. Molecular analysis of acid ceramidase deficiency in patients with 2018; 13(1):121. Farber disease. Hum Mutat. 2001; 17(3):199-209.

Page 4 of 4