ASAH1- Related Disorders

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 the age of onset and specific symptoms and severity. However, the current thinking is that these disorders are best thought of as a spectrum of diseases 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 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 walking 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 disorder in which fatty substances build up in various organs of the body causing severe enlargements 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 from 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 disorder 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 walking 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 reported in the medical literature had symptoms that overlapped between Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.