• Disease Overview
  • Synonyms
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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  • Complete Report

ASAH1-Related Disorders


Last updated: November 15, 2021
Years published: 1988, 1989, 1998, 2005, 2019, 2021


NORD gratefully acknowledges Jeffrey A. Medin, PhD, Departments of Pediatrics and Biochemistry, Medical College of Wisconsin, for assistance in the preparation of this report

Disease Overview

ASAH1-related disorders are an extremely rare group of disorders caused by an alteration (mutation) in the ASAH1 gene. Alterations in this gene result in a deficiency of the enzyme acid ceramidase. Enzymes are specialized proteins that act to bring about biochemical reactions in the body. The acid ceramidase enzyme is required to help break down certain fatty substances – called ceramides – in the body. Because the activity of this enzyme is reduced, these fatty substances build up abnormally in the cells and tissues of the body. This can cause a variety of signs and symptoms based on where the fatty substance builds up and how much of it builds up. The most common form of ASAH1-related disorder is called Farber disease, which can present in several different ways. The most common presentation is characterized by the three main symptoms: small bumps beneath the skin (subcutaneous nodules), joint disease, and hoarseness of voice. Some people will have additional symptoms, or different symptoms, that can include heart (cardiac), neurological, or breathing problems. A specific form of ASAH1-related disorder is called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), which is characterized by muscle weakness and degeneration, specifically in the legs, as well as seizures. ASAH1-related disorders can be best thought of as a spectrum of disease that can affect one person very differently from how it affects another person. This is true even for members of the same family. The signs, severity, and age of onset of symptoms can all be very different and can range from mild to severe. ASAH1-related disorders are inherited in an autosomal recessive manner.


ASAH1-related disorders are part of a group of hereditary metabolic diseases known as lysosomal storage disorders (LSDs). Lysosomes function as the primary digestive and recycling units within cells. Enzymes within lysosomes break down or digest particular cellular components, such carbohydrates, proteins and fats to their basic units which can then be recycled. Healthy cells and organs are constantly breaking down, recycling and building new cellular components. In individuals with these disorders, including ASAH1-related disorders, a deficiency of or improper functioning of lysosomal enzymes leads to an abnormal accumulation of particular substances such as fatty material called lipids. When cells cannot breakdown these fatty substances they can accumulate within various tissues of the body, such as the bones, joints, brain, heart, spleen, or liver and lead to the symptoms that affected individuals have.

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  • acid ceramidase deficiency
  • Farber disease
  • Farber lipogranulomatosis
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  • spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME)
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Signs & Symptoms

Although researchers have been able to establish clear syndromes with characteristic or “core” symptoms, much about these LSDs is not fully understood. Several factors including the small number of identified cases, the lack of large clinical natural history studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis. ASAH1-related disorders are also highly variable. This means how they affect one person can be significantly different from how they affect another person. ASAH1-related disorders can cause life-threatening complications in infants, or symptoms can develop in infancy and progressively worsen in children to varying degrees. In some people, the disorder may not be diagnosed until adulthood. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

The specific signs and symptoms, the age of onset, the progression and severity of the disorder, and the specific organ systems that are affected will vary from one person to another. Farber disease is the name used for the most common presentation of an ASAH1-related disorder. Sometimes, Farber disease is broken down into subtypes based on age of onset and specific symptoms and severity. However, the current thinking is that these disorders are best thought of as a spectrum of disease ranging from mild forms that can go undiagnosed into adulthood to forms that cause severe, even life-threatening complications in infancy.

Farber Disease Type 1

The classic form, sometimes called Farber disease type 1, is characterized by three main symptoms – skin nodules, joint disease, and hoarseness. Skin nodules are small lumps of cells and fat found just beneath the surface of the skin. These nodules can occur anywhere, but most often occur by the joints or mechanical pressure points, which are spots on the body that are especially sensitive to the application of pressure. Over time, the nodules may thicken and increase in number. These nodules are called lipogranulomas. Granulomas are nodules of inflamed tissue that are produced in response to a foreign substance or infection. In ASAH1-related disorders, this is in response to the abnormal buildup of fatty material (lipids) in the body.

Joint disease is characterized by swollen, stiff and painful joints that slowly worsen in severity. This can lead to progressive deformity of the affected joints. The wrists, elbows, hands, knees, and feet are most commonly affected. In severe instances, contractures may occur. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.

Hoarseness is also a common finding in Farber disease. Hoarseness is caused by the formation of nodules within the larynx. The larynx, which is also called the voice box, is the hollow organ at the top of the throat that contains the vocal cords. Affected infants may have a weak cry. As children age, they may have difficulty speaking clearly or easily (dysphonia), or they may be unable to speak (aphonia).

In some instances, nodules may affect the epiglottis. The epiglottis is a flap cartilage found in the back of the throat. When a person swallows, the epiglottis moves and covers the windpipe. This prevents food from “going down the wrong tube” and into the lungs. When nodules affect the epiglottis, swelling may occur and affected individuals may have trouble breathing and feeding. This can be severe.

The classic form of Farber disease can progress to cause lung and heart problems and problems with the brain and nervous system. Lung problems can include noisy breathing (stridor) when a child is breathing out (exhaling), labored or difficulty breathing, pneumonia, lung infection, and severe breathing problems (respiratory distress) that can be life-threatening.

Neurological findings can be broad and differ greatly among affected individuals. Some children may experience delays in reaching developmental milestones (developmental delays). This can progress to cause intellectual disability. Diminished muscle tone (hypotonia) and muscle weakness and degeneration (atrophy) can also occur and can progress to cause severe complications. Eventually, affected individuals may need assistance or walk or require a wheelchair.

Sometimes, problems with the eyes may develop including the formation of cherry red spots. This condition occurs when the macular cells of the eye deteriorate, exposing the underlying choroid. The choroid is the middle layer of the eye that consists of blood vessels that supply blood to the retina. Additional findings include the formations of nodules in the membrane lining the inner surface of the eyelids (conjunctiva), a poor ability to focus on (fixate on) objects, and rapid, involuntary eye movements (nystagmus).

Some individuals develop abnormal enlargement of the liver and spleen (hepatomegaly).

Farber Disease Type 2

This form is also characterized by the classic triad described above. Neurological problems can be present, but are usually less severe than seen in type 1. Seizures can also occur, and increase in frequency over time.

Farber Disease Type 3

The main symptom of this form is joint disease. Affected individuals develop swelling and pain in the affected joints that can progress to cause contractures. About half of affected individuals develop neurological problems and this form can be associated with below average IQ scores (cognitive deficit).

Farber Disease Type 4

This is a severe form of the disorder in which fatty substances build up in various organs of the body causing severe enlargement such as severe enlargement of the liver and spleen. The disorder is usually fatal within the first days to weeks of life.

Farber Disease Type 5

This form of the disorder is characterized by normal development for about 6 months to 1 year of age. Eventually, affected infants develop a variety of neurological problems and can lose previously acquired skills (regression) including speech. Seizures, which are resistant to treatment, can develop. There can also be partial paralysis of the legs (paraparesis). Skin nodules may occur and are usually mild. The lungs are usually not affected.

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME)

This is a distinct form of ASAH1-related disorders that is characterized by muscle weakness and seizures that are known as progressive myoclonic epilepsy. Muscle weakness starts in the proximal muscles of the legs, which are those closest to the center of the body (e.g. the muscles of the thighs) and progresses to affect the distal muscles, which are those further away from the center of the body (e.g. those of the lower legs). Affected individuals may be clumsy and fall frequently. Eventually, affected individuals have trouble walking or walk in a waddling manner (waddling gait). Over time, some individuals may require assistive devices like a cane to help them walk or, eventually, a wheelchair.

Progressive myoclonic epilepsy often occurs later in childhood after the development of muscle weakness and may be characterized by myoclonic and atonic seizures. Myoclonic seizures cause rapid, brief muscle contractions that cause sudden jerky or twitching movements. Jerking or spasms of the arms, jerking movements that occur when a person tries to voluntary move a muscle (action myoclonus), or jerking movements or spasms of the eyelids can occur. Atonic seizures are characterized by a sudden loss of muscle tone so that the head and body may go limp.

Some affected individuals develop additional symptoms including involuntary, rhythmic, movements of a body part (tremors), neurological problems that can lead to lower-than-average IQ scores (cognitive decline), or sensorineural hearing loss, which is hearing loss that occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself.

Children with spinal muscular atrophy and progressive myoclonic epilepsy have not developed characteristic skin nodules associated with Farber disease. However, at least one child report in the medical literature had symptoms that overlapped between Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

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ASAH1-related disorders are caused by variations (mutations) in the ASAH1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

The ASAH1 gene contains instructions for creating (encoding) an enzyme called acid ceramidase. This enzyme is essential for breaking down (hydrolysis) of a class of fatty substances called ceramides. There are many different ceramides in cells; they serve many normal functions. Because of the altered gene, people with this disorder have low activity levels of this enzyme, which means that ceramides build up abnormally in the various organ systems in the body, damaging the affected areas. Where and how much ceramide builds up can vary, which is why there are so many different the ways the disorder can appear in a person.

ASAH1-related disorders are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

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Affected populations

ASAH1-related disorders are extremely rare disorders. They affect males and females in equal numbers. Fewer than 200 individuals have been described in the medical literature. However, rare disorders like ASAH1-related disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

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A diagnosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in infants or children with characteristic early signs.

Clinical Testing and Workup

Individuals suspected of an ASAH1-related disorder will be tested to determine whether the activity of the enzyme, acid ceramidase, is reduced or absent. Certain cells, specifically certain white blood cells (peripheral blood leukocytes) or connective tissue cells (fibroblasts) will be used to assess how much acid ceramidase activity is present. In people with an ASAH1-related disorder, these tests, known as enzyme assays, will show a reduction in enzyme activity. Peripheral blood leukocytes are white blood cells that are drawn from the blood. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory.

Molecular genetic testing is often used to confirm a diagnosis. Molecular genetic testing can detect diseases-causing alterations (mutations) in the ASAH1 gene known to cause these disorders. In fact, some Farber patients have been identified in this manner. They had a variety of related symptoms and genomic sequencing confirmed that they had harmful variants in the ASAH1 gene.

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Standard Therapies

Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists), neurologists, physicians who specialize in the diagnosis and treatment of disorders of the bones and skeleton (orthopedists), physicians who specialize in the diagnosis and treatment of eye disorders (ophthalmologists), physicians who specialize in the diagnosis and treatment of skin disorders (dermatologists), speech pathologists, physical therapists, pain specialists, and other healthcare professionals may need to systematically and comprehensively plan treatment.

Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.

There is presently no cure for ASAH1-related disorders and there are no standardized treatment protocols or guidelines for affected individuals. To date, treatment is aimed at the specific symptoms that are present in each individual. Seizures may be treated with drugs that reduce the seizure occurrence (anti-epileptics). Some infants may need to undergo surgical removal of nodules that form in the airways or mouth cavity. Sometimes, a tracheostomy may be required. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Some affected children may need a gastrostomy tube, in which a small, thin tube that is inserted into the stomach through a small cut in the abdomen to allow the passage of food and liquid.

Anti-inflammatory medications and physical therapy can help to reduce or improve mobility issues and pain associated with joint disease. Surgery may be necessary for the removal of nodules in the hand.

Individuals with SMA-PME may be treated with anti-seizure mediations, standard medications for the treatment of tremors, a gastrostomy tube, and standard treatment for scoliosis. Some individuals may require breathing (respiratory) therapy and standard therapy for treating recurrent pneumonia. Sometimes, noninvasive ventilatory support or a tracheostomy may be necessary. Some individuals may require assistive devices to walk including special shoes, walkers, or wheelchairs.

Following an initial diagnosis, it is recommended that a developmental assessment be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. A developmental pediatrician can help with management of behavioral issues and medication considerations.

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Clinical Trials and Studies

Researchers are studying enzyme replacement therapy (ERT) for lysosomal storage diseases such as ASAH1-related disorders. ERT involves replacing a missing enzyme in individuals who are deficient or lack the particular enzyme in question. Synthetic versions of missing enzymes have been developed and used to treat individuals with certain lysosomal diseases including Hurler syndrome, Fabry disease, and Gaucher disease. Clinical trials are necessary to determine whether ERT will be safe and effective for the treatment of ASAH1-related disorders.

Gene therapy is also being studied as another approach to therapy for individuals with Farber disease. In gene therapy, the defective gene present in a patient is augmented with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a sustained correction of the disease.

Some children have been treated with hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells – red blood cells, white blood cells or platelets. A transplant is done to replace the bone marrow (and consequently the whole blood system) of an affected individual with marrow from a person who does not have a particular disorder. Individuals with Farber disease treated with hematopoietic stem cell transplantation have shown improvement of skin (cutaneous) and joint problems associated with the disorder. However, this therapy does not alter the progression of motor neuron disease or other neurological complications. More research is necessary to determine the long-term safety and effectiveness of this potential therapy for affected infants. Hematopoietic stem cell transplants are not without drawbacks. The procedure is expensive and carries the risk of serious complications including graft-versus-host disease and other long-term and late effects. HSCT can be used to treat affected individuals without significant neurological involvement.

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:

For information about clinical trials sponsored by private sources, contact:

For information about clinical trials conducted in Europe, contact:

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Axente M, Shelby E-S, Mirea A, et al. Clinical features and genetics in non-5q spinal muscular atrophy caused by acid ceramidase deficiency. J Med Life. May-Jun 2021;14(3):424-428. https://pubmed.ncbi.nlm.nih.gov/34377212/

Puma A, Ezaru A, Cavalli M, et al. A case of ASAH1-related pure SMA evolving into adult-onset Farber disease. Clin Genet. 2021 Aug;100(2):234-235. https://pubmed.ncbi.nlm.nih.gov/34240417/

Lee BH, Mongiovi P, Levade T, Marston B, Mountain J and Ciafaloni E. Spinal muscular atrophy and Farber disease due to ASAH1 variants: A case report. AJMG. Part A. 2020; 182(10):2369-2371. https://europepmc.org/article/med/32627310

Yu FPS, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis. 2018;13:121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053731/

Yu FPS, Dworski S, Medin JA. Deletion of MCP-1 impedes pathogenesis of acid ceramidase deficiency. Sci Rep. 2018;8:1808. https://www.ncbi.nlm.nih.gov/pubmed/29379059

Zielonka M, Garbade SF, Kolker S, Hoffmann GF, Ries M. A cross-sectional quantitative analysis of the natural history of Farber disease: an ultra-orphan condition with rheumatologic and neurological cardinal disease features. Genet Med. 2018;20:2017. https://www.ncbi.nlm.nih.gov/pubmed/29048419

Dworski S, Lu P, Khan A, et al. Acid ceramidase deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy. Biochim Biophys Acta Mol Basis Dis. 2017;1863:386-394. https://www.ncbi.nlm.nih.gov/pubmed/27915031

Cozma C, Iurascu MI, Eichler S, et al. C26-ceramide as highly sensitive biomarker for the diagnosis of Farber disease. Sci Rep. 2017;7:6149. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522391/

He X, Dworski S, Zhu C, et al. Enzyme replacement therapy of Farber disease: proof-of-concept studies in cells and mice. BBA Clin. 2017;7:85-96. https://www.ncbi.nlm.nih.gov/pubmed/28275553

Bonafe L, Kariminejad A, Li J, et al. Brief Report: Peripheral osteolysis in adults linked to ASAH1 (acid ceramidase) mutations: a new presentation of Farber’s disease. Arthritis Rheumatol. 2016 Sep;68(9):2323-7. https://pubmed.ncbi.nlm.nih.gov/26945816/

Schuchman EH. Acid ceramidase and the treatment of ceramide diseases: the expanding role of enzyme replacement therapy. Biochim Biophys Acta. 2016;1862:1459-1471. https://www.ncbi.nlm.nih.gov/pubmed/27155573

Torcoletti M, Petaccia A, Pinto RM, et al. Farber disease in infancy resembling juvenile idiopathic arthritis: identification of two new mutations and a good early response allogeneic haematopoietic stem cell transplantation. Rheumatology (Oxford). 2014;53:1533-1534. https://www.ncbi.nlm.nih.gov/pubmed/24614645

Sands MS. Farber diseases: understanding a fatal childhood disorder and dissecting ceramide biology. EMBO Mol Med. 2013;5:799-801. https://www.ncbi.nlm.nih.gov/pubmed/23666771


Dyment DA, Bennett SAL, Medin JA, et al. ASAH1-Related Disorders. 2018 Mar 29. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK488189/ Accessed November 8, 2021.

Farber Lipogranulomatosis.Medline Plus. December 2013. Available at: https://ghr.nlm.nih.gov/condition/farber-lipogranulomatosis# Accessed November 8, 2021.

Levade T. Farber Disease.Orphanet Encyclopedia. April 2019. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=333 Accessed November 8, 2021.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University; Entry No:228000; Last Update: 10/04/2021. Available at: https://www.omim.org/entry/228000 Accessed November 8, 2021.

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