Mucolipidosis IV

Mucolipidosis type IV (MLIV) is a severe and recently identified genetic disease inherited as an autosomal recessive trait. It is a lysosomal disease that affects the brain with impaired motor and cognitive development, progressive loss of vision – and gastric achlorhydria (lack of gastric acid production).

The disease is over-represented in the Ashkenazim and although the causal genetic locus maps to chromosome 19 and mutations in the MCOLN4 gene are known to cause the condition, exactly how the severe psychomotor retardation is brought about is unknown.

At present, no definitive therapy for MLIV is available. White matter abnormalities and a hypoplastic corpus callosum are often identified on imaging of the brain. Most cases of this autosomal recessive condition are severe, with onset in the first year of life; milder cases have also been reported.

MLIV is one of a group of conditions called lysosomal disorders.

Presentation

  • Psychomotor retardation; similar to cerebral palsy; usually presenting by the end of the first year of life.
  • Mental retardation
  • Children typically reach a maximum developmental age of 15 months in language and motor function
  • Receptive abilities are better than expressive abilities
  • Hypotonia
  • Tendon reflexes are usually spastic
  • Corneal clouding
  • Pseudo-strabismus
  • Progressive retinal degeneration, resulting in severe visual impairment or blindness by the late teenage years
  • The majority of MLIV patients appear to have a static encephalopathy and do not deteriorate neurologically, however some patients show a decline in motor function in the second or third decade of life
  • Prior to the availability of molecular diagnosis of MLIV, individuals with atypical MLIV were thought to have cerebral palsy, suggesting that MLIV is under diagnosed

Please click on the titles to open and close the following information sections.

  • MLIV is caused by mutations in a gene MCOLN1 localised on the short arm of chromosome 19 (19p13.2).
  • This gene encodes mucolipin-1 (ML-1), a non-selective cation channel.
  • Disease-causing mutations (which are usually inherited from both parents, who from this aspect are perfectly healthy), disrupt cellular functions and induce accumulate auto-fluorescent vacuoles in neurons and other related cells; these vacuoles are considered to be aberrant lysosomes. Defective exocytosis and endocytosis has been reported.
  • The exact mechanism by which MCOLN1 mutations cause MLIV is not completely understood but as with other lysosomal diseases, the disease is associated with an inability of the body to move lipids and other substances properly within cells, causing an ill-understood toxicity in the organs that are vital for life, including the brain.
  • Although MLIV can affect individuals of all ethnicities it is estimated that approximately 70% of individuals with MLIV are of Ashkenazi Jewish (AJ) ancestry.
  • Among AJ the carrier frequency is approximately 1:100; with the disease incidence being estimated as 1:40,000
  • 2 mutations account for approximately 95% of all Ashkenazi Jewish MLIV cases.
  • MLIV, the most severe form of four types of Mucolipidosis, is the only one that is relatively more prevalent in people of AJ ancestry.

Gene Specific:

  • MCOLN1 is the only gene known to be associated with MLIV.
  • Clinical diagnosis can be confirmed via genetic testing; this approach is often more streamlined for the relevant and widespread mutations in the MCOLN1 gene.

Other supporting evidence:

  • MRI brain at the time of diagnosis shows a dysplastic corpus callosum and demyelinating white matter abnormalities.
  • All patients have constitutive achlorhydria associated with a secondary elevation of plasma gastrin levels.
  • Biopsy of skin or conjunctiva shows accumulation of abnormal lamellar membrane structures and amorphous cytoplasmic inclusions in diverse cell types.
  • Cerebellar atrophy is seen predominantly in older patients.

Management is symptomatic and supportive, and includes:

  • Physical therapy for spasticity, ataxia and the prevention of joint contractures.
  • Topical lubricating eye drops, artificial tears, gels or ointments for ocular irritation.
  • Surgical correction of strabismus.
  • Oral iron to prevent iron deficiency anaemia due to poor absorption of dietary iron (unknown efficacy on the speed of resolution and recovery).
  • Corneal clouding may at least temporarily corrected by corneal transplantation.

Family members should be offered genetic counselling and testing. Carrier testing and pre-natal testing is available for this condition.

Individuals with MLIV typically survive to adulthood, although it is believed that their life expectancy is reduced compared to healthy individuals.

  •  For children exhibiting features of Mucolipidosis IV (MLIV), initial referral would usually be to a paediatrician. For Jewish patients, it is important to note the child’s ancestry and higher prevalence of MLIV in the Jewish population.
  •  For patients that have received a positive MLIV diagnosis:
    • On-going management is usually under the care of a paediatrician with other specialist input as appropriate.
    • Families may benefit from referral to a clinical genetics department to establish carrier status in other family members as appropriate.
The Society For Mucopolysaccharide Diseases

This UK-based charity represents people affected by a mucopolysaccharide or related lysosomal storage disease, including ML4. The Society’s include: providing information about the diseases, offering a range of support services, and promoting and supporting research.

Phone: 0845 389 9901.

Mucolipidosis IV Foundation (USA)

The ML4 Foundation is USA-based non-profit organisation that funds, promotes, and supports medical research dedicated to developing effective treatments and cures for ML4. The site provides information, discussion forums and links to news and resources relating to ML4.

ML4 Facebook Group

A Facebook Group supported by the ML4 Foundation.

GeneReviews: www.ncbi.nlm.nih.gov/books/NBK1214

OMIM: #252650

Written by: Dr Jacky Megitt, Jnetics researcher.
Approved by: Professor Tim Cox, Director of Research and Honorary Consultant Physician, University of Cambridge, Addenbrooke’s Hospital.
Last review: 28.04.2016

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