Mucolipidosis III alpha/beta

Alternate names

ML3; ML 3 A; Pseudo-Hurler polydystrophy; Mucolipidosis type 3A

Definition

Mucolipidosis III (ML III) is a rare and progressive metabolic disorder that involves our body’s ability to break down certain fats (mucolipids).

Onset

Signs and symptoms of this condition typically appear around age 3 and worsen slowly over time.

Epidemiology

Mucolipidosis III alpha/beta is a rare disorder, although its exact prevalence is unknown. It is estimated to occur in about 1 in 100,000 to 400,000 individuals worldwide.

Cause

Mutations in the GNPTAB gene cause mucolipidosis III alpha/beta. This gene provides instructions for making a part (subunit) of an enzyme called GlcNAc-1-phosphotransferase. This enzyme helps prepare certain newly made enzymes for transport to lysosomes. Lysosomes are compartments within the cell that use digestive enzymes to break down large molecules into smaller ones that can be reused by cells. GlcNAc-1-phosphotransferase is involved in the process of attaching a molecule called mannose-6-phosphate (M6P) to specific digestive enzymes. Just as luggage is tagged at the airport to direct it to the correct destination, enzymes are often "tagged" after they are made so they get to where they are needed in the cell. M6P acts as a tag that indicates a digestive enzyme should be transported to the lysosome.

Gene mutations

• Mutations in the GNPTAB gene that cause mucolipidosis III alpha/beta result in reduced activity of GlcNAc-1-phosphotransferase.
• These mutations disrupt the tagging of digestive enzymes with M6P, which prevents many enzymes from reaching the lysosomes.
• Digestive enzymes that do not receive the M6P tag end up outside the cell, where they have increased activity.
• The shortage of digestive enzymes within lysosomes causes large molecules to accumulate there.
• Conditions that cause molecules to build up inside lysosomes, including mucolipidosis III alpha/beta, are called lysosomal storage disorders.
• The signs and symptoms of mucolipidosis III alpha/beta are most likely due to the shortage of digestive enzymes inside lysosomes and the effects these enzymes have outside the cell.
• Mutations in the GNPTAB gene can also cause a similar but more severe disorder called mucolipidosis II alpha/beta. These mutations completely eliminate the function of GlcNAc-1-phosphotransferase.
• Mucolipidosis III alpha/beta and mucolipidosis II alpha/beta represent two ends of a spectrum of disease severity.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Individuals with mucolipidosis III alpha/beta grow slowly and have short stature. They also have stiff joints and dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Many affected individuals develop low bone mineral density (osteoporosis), which weakens the bones and makes them prone to fracture. Osteoporosis and progressive joint problems also cause bone pain that becomes more severe over time in people with mucolipidosis III alpha/beta. People with mucolipidosis III alpha/beta often have heart valve abnormalities and mild clouding of the clear covering of the eye (cornea). Their facial features become slightly thickened or "coarse" over time. Affected individuals may also develop frequent ear and respiratory infections. About half of people with this condition have mild intellectual disability or learning problems. Individuals with mucolipidosis III alpha/beta generally survive into adulthood, but they may have a shortened lifespan.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal form of the vertebral bodies
• Cognitive impairment(Abnormality of cognition)
• Craniofacial hyperostosis(Excessive bone growth of the skull and face)
• Hearing abnormality(Abnormal hearing)
• Hypoplastic inferior ilia
• Joint stiffness(Stiff joint)
• Large iliac wings
• Prominent occiput(Prominent back of the skull)
• Short stature(Decreased body height)
• Visual impairment(Impaired vision)

30%-79% of people have these symptoms

• Acne
• Coarse facial features(Coarse facial appearance)
• Corneal opacity
• Hyperlordosis(Prominent swayback)
• Inguinal hernia

5%-29% of people have these symptoms

• Abnormal aortic valve morphology
• Cleft palate(Cleft roof of mouth)
• Fatigue(Tired)
• Reduced bone mineral density(Low solidness and mass of the bones)

Diagnosis

• In ML III alpha/beta the activity of nearly all lysosomal hydrolases is up to tenfold higher in plasma and other body fluids than in normal controls because of inadequate targeting to lysosomes.
• Urinary excretion of oligosaccharides (OSs), a nonspecific finding, is often excessive.
• Significant deficiency (1%-10% of normal) of the activity of the enzyme UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (GNPTA), encoded by GNPTAB, confirms the diagnosis.
• Bidirectional sequencing of the entire GNPTAB coding region detects two pathogenic variants in more than 95% of individuals with ML III alpha/beta.

Treatment

Low-impact physical therapy is usually well tolerated. Myringotomy tube placement may be indicated in the treatment of recurrent otitis media. Carpal tunnel signs may require tendon release. In late childhood or early adolescence symptomatic relief of hip pain may be initially accomplished with over-the-counter analgesics; in some older adolescents and adults with milder phenotypic variants, bilateral hip replacement has been successful. Later in the disease course management focuses on relief of general bone pain associated with osteoporosis, which has responded in a few individuals to scheduled intermittent IV administration of the bisphosphonate pamidronate.

NIH genetic and rare disease info

• NIH info on Mucolipidosis III alpha/beta

Mucolipidosis III alpha/beta is a rare disease.

Mucolipidosis III alpha/beta Resources
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