The symptoms, progression and severity of alpha-mannosidosis vary widely from one person to another, including between siblings who share the same mutation. Alpha-mannosidosis represents a spectrum or continuum of disease and is highly individualized. Some individuals develop symptoms shortly after birth and may develop potentially life-threatening complications in infancy or early childhood. Other individuals develop more moderate symptoms usually with onset before the age of 10. In some cases, individuals may not be diagnosed until adulthood.
The disorder is generally broken down into three separate subtypes: mild (type 1), moderate (type 2) and severe (type 3). Most affected individuals fall into the moderate subtype. It is important to note, because of the highly variable nature of the disorder, that affected individuals will not have all of the symptoms discussed below.
The mild form (type 1) may not be evident until the teen years and progresses slowly. Symptoms typically include muscle weakness. Skeletal abnormalities are usually not present. The person with type 1 may have normal cognitive and physical development. However, even this later-onset form may be accompanied by mild to moderate intellectual disability. In some cases, the clinical progression of the disease appears to slow down or stop as the affected individual grows beyond school age.
In the moderate form of the disorder (type 2), signs of Skeletal abnormalities and Muscle Weakness may appear before ten years of age and progress slowly. Ataxia (an impaired ability to coordinate voluntary movements) may develop by the age of 20-30.
The severe form (type 3) begins within the first year of life. In most cases, infants appear normal at birth, but the condition grows progressively worse. Type 3 alpha-mannosidosis is characterized by rapid progression of intellectual disability, hydrocephalus, progressive impairment of the ability to coordinate voluntary movements (ataxia), enlargement of the liver and spleen (hepatosplenomegaly), skeletal abnormalities, and coarse facial features.
Intellectual disabilities associated with alpha-mannosidosis can range from mild Cognitive impairment to profound mental deficiency. The severity can vary dramatically even among siblings. Children often experience delays achieving the ability to speak, and their speech stays blured.
Motor skills may also be affected in alpha-mannosidosis. Affected children may experience delays in learning to walk and may appear clumsy. Diminished muscle tone (hypotonia) is often present.
Many individuals with alpha-mannosidosis develop moderate to severe hearing loss. Hearing loss is caused by a defect of the inner ear or the auditory nerve that prevents sound vibrations from being transmitted to the brain (With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain.). Hearing can worsen even further with otitis with accumulation of fluid in the middle ear.
The Skeletal abnormalities associated with type 2 and type 3 may include facial abnormalities such as a Prominent forehead and jaw, and a flattened nose. Affected children may be especially prone to dental problems such as cavities. In addition, some infants are born with an abnormally twisted ankle (ankle equinus) or hydrocephalus, a condition in which the accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain.
Types 2 and 3 also may be characterized by Distinctive facial features including widely spaced or unevenly developed teeth, a thickened, enlarged tongue (macroglossia), prominent forehead, flattened nasal bridge, and a protruding lower jaw (prognathism). Abnormalities affecting the eyes may include an inability to align the eyes (strabismus or crossed eyes), clouding (opacity) of the transparent outer covering of the eye (cornea), and farsightedness (hyperopia) and, less commonly, Nearsightedness (myopia).
Growth rates can fluctuate with accelerated early growth but subsequent impaired growth, causing short stature. Thin arms and/or legs with stiff joints may develop. Spinal abnormalities may lead to extreme curvature in some cases. Over time, affected individuals may eventually develop degenerative disease affecting multiple joints (destructive polyarthropathy).
In type 3 disease, a diminished or abnormal immune system response can make affected individuals more susceptible to bacterial infections, particularly of the respiratory system. Infections affecting the middle ear and gastrointestinal tract are also common. Recurrent infections are more common during the first decade of life.
Some individuals with alpha-mannosidosis develop psychiatric abnormalities such as confusion, anxiety, Depression or hallucinations. These symptoms may persist for days or weeks, followed by a need for excessive amounts of sleep (hypersomnia). Psychiatric symptoms or behavioral problems occur in almost half of those affected and usually develop during adolescence or early adulthood.