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Farber lipogranulomatosis(FRBRL)

MedGen UID:
78654
Concept ID:
C0268255
Disease or Syndrome
Synonyms: AC deficiency; Acid ceramidase deficiency; Ceramidase deficiency; Farber disease; Farber's disease; Farber's lipogranulomatosis; FRBRL; N-Laurylsphingosine deacylase deficiency
SNOMED CT: Farber lipogranulomatosis (79935000); Ceramidase deficiency (79935000); Farber disease (79935000); Farber's lipogranulomatosis (79935000); Farber's disease (79935000); Acid ceramidase deficiency (79935000); Disseminated lipogranulomatosis (79935000); Farber-Uzman syndrome (79935000); Acylsphingosine deacylase deficiency (79935000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ASAH1 (8p22)
 
Monarch Initiative: MONDO:0009218
OMIM®: 228000
Orphanet: ORPHA333

Disease characteristics

Excerpted from the GeneReview: ASAH1-Related Disorders
The spectrum of ASAH1-related disorders ranges from Farber disease (FD) to spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary. SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years. [from GeneReviews]
Authors:
David A Dyment  |  Steffany AL Bennett  |  Jeffrey A Medin, et. al.   view full author information

Additional descriptions

From OMIM
Farber lipogranulomatosis is an autosomal recessive lysosomal storage disorder characterized by early-onset subcutaneous nodules, painful and progressively deformed joints, and hoarseness by laryngeal involvement. Based on the age of onset, the severity of symptoms, and the difference in organs affected, 6 clinical subtypes due to deficiency of acid ceramidase have been distinguished. The most severe form is subtype 4, a rare neonatal form of the disease with death occurring before 1 year of age (summary by Alves et al., 2013).  http://www.omim.org/entry/228000
From MedlinePlus Genetics
Farber lipogranulomatosis is a rare inherited condition involving the breakdown and use of fats in the body (a process known as lipid metabolism). In affected individuals, lipids accumulate abnormally in cells and tissues throughout the body, particularly around the joints. Researchers had previously categorized Farber lipogranulomatosis into subtypes based on characteristic features, but the condition is now thought to be a spectrum of overlapping signs of symptoms.

Three classic signs occur in Farber lipogranulomatosis: a hoarse voice or a weak cry, small lumps of fat under the skin and in other tissues (lipogranulomas), and swollen and painful joints. Signs and symptoms typically first develop in infancy.

In addition to the classic signs, Farber lipogranulomatosis often affects multiple body systems. Affected individuals can have developmental delay, behavioral problems, or seizures. In severe cases, people experience progressive decline in brain and spinal cord (central nervous system) function, a buildup of fluid in the brain (hydrocephalus), loss (atrophy) of brain tissue, paralysis of the arms and legs (quadriplegia), loss of speech, or involuntary muscle jerks (myoclonus).  

People with Farber lipogranulomatosis often have enlarged liver, spleen, and immune system tissues due to massive lipid deposits. Lipid deposits may also occur in the eyes and lungs, leading to vision problems and breathing difficulty. Affected individuals may develop thinning of the bones (osteoporosis) that worsens over time.

Because of the severity of the signs and symptoms of the condition, individuals with Farber lipogranulomatosis generally do not survive past childhood.  https://medlineplus.gov/genetics/condition/farber-lipogranulomatosis

Clinical features

From HPO
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Ulnar deviation of the wrist
MedGen UID:
115906
Concept ID:
C0231678
Sign or Symptom
Acroosteolysis
MedGen UID:
183017
Concept ID:
C0917990
Disease or Syndrome
Dissolution or degeneration of bone tissue of the phalanges of the hand.
Limitation of knee mobility
MedGen UID:
866903
Concept ID:
C4021259
Finding
An abnormal limitation of knee joint mobility.
Osteolysis involving bones of the feet
MedGen UID:
870147
Concept ID:
C4024579
Disease or Syndrome
Cherry red spot of the macula
MedGen UID:
786046
Concept ID:
C2216370
Finding
Pallor of the perifoveal macula of the retina with appearance of a small circular reddish choroid shape as seen through the fovea centralis due to relative transparency of the macula.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Arthritis
MedGen UID:
2043
Concept ID:
C0003864
Disease or Syndrome
Inflammation of a joint.
Joint swelling
MedGen UID:
56258
Concept ID:
C0152031
Finding
The presence of swelling in a joint.
Hyperextensibility of the finger joints
MedGen UID:
334982
Concept ID:
C1844577
Finding
The ability of the finger joints to move beyond their normal range of motion.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.
Decreased acid ceramidase activity
MedGen UID:
1814226
Concept ID:
C5676653
Finding
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
Hoarse cry
MedGen UID:
394791
Concept ID:
C2678303
Finding
Subcutaneous nodule
MedGen UID:
101803
Concept ID:
C0151811
Pathologic Function
Slightly elevated lesions on or in the skin with a diameter of over 5 mm.
Periarticular subcutaneous nodules
MedGen UID:
812636
Concept ID:
C3806306
Finding
Subcutaneous nodules that are located in the vicinity of joints.
Lipogranulomatosis
MedGen UID:
316438
Concept ID:
C1704214
Disease or Syndrome
Yellow nodules of lipoid material are deposited in the skin and mucosae. This gives rise to granulomatous reactions.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVFarber lipogranulomatosis

Professional guidelines

PubMed

Schuchman EH
Biochim Biophys Acta 2016 Sep;1862(9):1459-71. Epub 2016 May 4 doi: 10.1016/j.bbadis.2016.05.001. PMID: 27155573

Recent clinical studies

Etiology

Cozma C, Hovakimyan M, Iurașcu MI, Makhseed N, Selim LA, Alhashem AM, Ben-Omran T, Mahmoud IG, Al Menabawy NM, Al-Mureikhi M, Martin M, Demuth L, Yüksel Z, Beetz C, Bauer P, Rolfs A
Orphanet J Rare Dis 2019 Aug 27;14(1):209. doi: 10.1186/s13023-019-1183-5. PMID: 31455396Free PMC Article
Schuchman EH
Biochim Biophys Acta 2016 Sep;1862(9):1459-71. Epub 2016 May 4 doi: 10.1016/j.bbadis.2016.05.001. PMID: 27155573
Ramsubir S, Nonaka T, Girbés CB, Carpentier S, Levade T, Medin JA
Mol Genet Metab 2008 Nov;95(3):133-41. Epub 2008 Sep 20 doi: 10.1016/j.ymgme.2008.08.003. PMID: 18805722Free PMC Article

Diagnosis

Alamri AS, Alshowaeir DA, AlFaiz AA, Al Mousawi FH, Mahmoud AA, Alhashim AH
J Neuroophthalmol 2019 Sep;39(3):391-393. doi: 10.1097/WNO.0000000000000795. PMID: 31022067
Yu FPS, Amintas S, Levade T, Medin JA
Orphanet J Rare Dis 2018 Jul 20;13(1):121. doi: 10.1186/s13023-018-0845-z. PMID: 30029679Free PMC Article
Cappellari AM, Torcoletti M, Triulzi F, Corona F
J Inherit Metab Dis 2016 Jan;39(1):149-50. Epub 2015 Sep 15 doi: 10.1007/s10545-015-9890-0. PMID: 26373951
Cvitanovic-Sojat L, Gjergja Juraski R, Sabourdy F, Fensom AH, Fumic K, Paschke E, Levade T
Eur J Paediatr Neurol 2011 Mar;15(2):171-3. Epub 2010 Jul 7 doi: 10.1016/j.ejpn.2010.06.002. PMID: 20609603
Mondal RK, Nandi M, Datta S, Hira M
Indian Pediatr 2009 Feb;46(2):175-7. PMID: 19242039

Therapy

Sears SM, Dupre TV, Shah PP, Davis DL, Doll MA, Sharp CN, Vega AA, Megyesi J, Beverly LJ, Snider AJ, Obeid LM, Hannun YA, Siskind LJ
J Lipid Res 2022 Mar;63(3):100179. Epub 2022 Feb 10 doi: 10.1016/j.jlr.2022.100179. PMID: 35151662Free PMC Article
Ahmad M, Hermanson ME, Enzenauer R, Palestine A, Lin C, Meeks N, McCourt E
J AAPOS 2017 Jun;21(3):249-251. Epub 2017 May 19 doi: 10.1016/j.jaapos.2017.05.011. PMID: 28532706
Schuchman EH
Biochim Biophys Acta 2016 Sep;1862(9):1459-71. Epub 2016 May 4 doi: 10.1016/j.bbadis.2016.05.001. PMID: 27155573
Cappellari AM, Torcoletti M, Triulzi F, Corona F
J Inherit Metab Dis 2016 Jan;39(1):149-50. Epub 2015 Sep 15 doi: 10.1007/s10545-015-9890-0. PMID: 26373951
Ramsubir S, Nonaka T, Girbés CB, Carpentier S, Levade T, Medin JA
Mol Genet Metab 2008 Nov;95(3):133-41. Epub 2008 Sep 20 doi: 10.1016/j.ymgme.2008.08.003. PMID: 18805722Free PMC Article

Prognosis

Bao X, Ma M, Zhang Z, Xu Y, Qiu Z
Am J Med Genet A 2020 Sep;182(9):2184-2186. Epub 2020 Jul 24 doi: 10.1002/ajmg.a.61752. PMID: 32706452
Ehlert K, Levade T, Di Rocco M, Lanino E, Albert MH, Führer M, Jarisch A, Güngör T, Ayuk F, Vormoor J
J Inherit Metab Dis 2019 Mar;42(2):286-294. Epub 2019 Feb 27 doi: 10.1002/jimd.12043. PMID: 30815900
Nivaggioni V, Cano A, Arnoux I, Michel G, Loosveld M
Br J Haematol 2016 Oct;175(2):189. Epub 2016 Jul 29 doi: 10.1111/bjh.14265. PMID: 27471081
Cvitanovic-Sojat L, Gjergja Juraski R, Sabourdy F, Fensom AH, Fumic K, Paschke E, Levade T
Eur J Paediatr Neurol 2011 Mar;15(2):171-3. Epub 2010 Jul 7 doi: 10.1016/j.ejpn.2010.06.002. PMID: 20609603
Kim YJ, Park SJ, Park CK, Kim SH, Lee CW
J Korean Med Sci 1998 Feb;13(1):95-8. doi: 10.3346/jkms.1998.13.1.95. PMID: 9539328Free PMC Article

Clinical prediction guides

He X, Schuchman EH
Biomolecules 2023 Nov 6;13(11) doi: 10.3390/biom13111623. PMID: 38002305Free PMC Article
Mhatre S, Muranjan M, Karande S, Balaji H
BMJ Case Rep 2021 May 27;14(5) doi: 10.1136/bcr-2020-240742. PMID: 34045195Free PMC Article
Elsea SH, Solyom A, Martin K, Harmatz P, Mitchell J, Lampe C, Grant C, Selim L, Mungan NO, Guelbert N, Magnusson B, Sundberg E, Puri R, Kapoor S, Arslan N, DiRocco M, Zaki M, Ozen S, Mahmoud IG, Ehlert K, Hahn A, Gokcay G, Torcoletti M, Ferreira CR
Hum Mutat 2020 Sep;41(9):1469-1487. Epub 2020 Jun 24 doi: 10.1002/humu.24056. PMID: 32449975
Cozma C, Hovakimyan M, Iurașcu MI, Makhseed N, Selim LA, Alhashem AM, Ben-Omran T, Mahmoud IG, Al Menabawy NM, Al-Mureikhi M, Martin M, Demuth L, Yüksel Z, Beetz C, Bauer P, Rolfs A
Orphanet J Rare Dis 2019 Aug 27;14(1):209. doi: 10.1186/s13023-019-1183-5. PMID: 31455396Free PMC Article
Bonafé L, Kariminejad A, Li J, Royer-Bertrand B, Garcia V, Mahdavi S, Bozorgmehr B, Lachman RL, Mittaz-Crettol L, Campos-Xavier B, Nampoothiri S, Unger S, Rivolta C, Levade T, Superti-Furga A
Arthritis Rheumatol 2016 Sep;68(9):2323-7. Epub 2016 Jul 29 doi: 10.1002/art.39659. PMID: 26945816

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