Mucolipidosis

What is Mucolipidosis?

It is a group of metabolic diseases, also known as lysosomal storage diseases, all of which are inherited. There are four main types of Mucolipidosis diseases.

They affect the body’s renewal of material within cells. This in turn leads to a build up of higher than normal levels of carbohydrates and lipids (fatty materials) in the cells. This then creates damage to the cells and triggers the symptoms related to Mucolipidosis syndromes.

In some affected individuals the symptoms are present at birth, in early childhood or eventually during adolescence. The main symptoms, including intellectual disability, are progrssive and may worsen with time.

Syndrome Synonyms:
Ml Iv; Ml4 ML4 MLIV Sialolipidosis

What gene changes cause Mucolipidosis?

A genetic defect is responsible for causing the syndrome.The genes responsible include, GNPTAB, GNPTAG, and MCOLN1. Affected individuals are born with an inability to produce enough enzymes to break down carbohydrates and lipids.

These rare diseases are inherited in an autosomal recessive pattern. Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

What are the main symptoms of Mucolipidosis?

The symptoms vary according to the type of Mucolipidosis an individual has.

Mucolipidosis type I (ML I): swelling over the whole body usually present at birth, large tongue, flat nasal bridge, and enlarged gums. Other symptoms include skeletal abnormalities, seizures, tremors, failure to thrive and respiratory infections. Life expectancy is rarely beyond one year.

Mucolipidosis types II and III (ML II and ML III): symptoms of type II of the disease are often severe. They include coarse facial features, skeletal abnormalities, enlarged liver and spleen, short-trunk dwarfism and recurrent respiratory infections. Life expectancy with this type is generally below 7 years.

Symptoms of type III include skeletal abnormalities, coarse facial features and closing of the corneas. This is the most mild form of the disease, and affected individuals generally have normal intellectual ability. Life expectancy reaches into adulthood.

Mucolipidosis type IV (ML IV): main symptoms include gross motor delay, most affected individuals are not able to walk independently. Impaired vision is another major symptom. In some cases affected individuals may have even milder symptoms.

Possible clinical traits/features:
Incoordination, Cognitive impairment, Opacification of the corneal stroma, Gait disturbance, Genu recurvatum, Hyperreflexia, Microcephaly, Strabismus, Spastic tetraplegia, Infantile onset, Progressive retinal degeneration, Retinopathy, Palmoplantar keratoderma, Photophobia, Optic atrophy, Nystagmus, Autosomal recessive inheritance, Dystonia, Dysplastic corpus callosum, EEG abnormality, Everted lower lip vermilion, Decreased light- and dark-adapted electroretinogram amplitude, Coarse facial features, Developmental stagnation, Neurological speech impairment, Narrow forehead, Intellectual disability, Muscular hypotonia, Microdontia, Abnormal nasal morphology, Ganglioside accumulation, Abnormal electroretinogram, Abnormality of mucopolysaccharide metabolism, Abnormality of abdomen morphology, Abnormality of retinal pigmentation, Cerebellar atrophy, Cerebral dysmyelination, Aplasia/Hypoplasia of the abdominal wall musculature, Absent speech, Babinski sign

How does someone get tested for Mucolipidosis?

The initial testing for Mucolipidosis can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Mucolipidosis

Syndrome Overview:
Mucolipidosis IV is a neurodegenerative lysosomal storage disorder characterized by severe psychomotor delay and progressive visual impairment. Corneal clouding, retinal degeneration, increased blood gastrin levels and iron defficiency anemia are common manifestations. Mutations in the MCOLN1 gene cause this autosomal recessive disorder.

Clinical Description:
The main features of this condition are intellectual disability and clouding of the corneas, but the presentation can vary widely. Severe developmental delay, spasticity, hypotonia and the inability to walk independently are common and typically begin in early childhood. The MRI is thought to be characteristic (Frei et al., 1998). There is hypoplasia of the corpus callosum, with absent rostrum and a dysplastic or absent splenium, T1-weighted white matter changes and increased ferritin deposits in the thalami and basal ganglia. In the later stages of the disease, optic atrophy and a pigmentary retinopathy become apparent.
Cytoplasmic inclusions - in both single membrane-bound vesicles filled with granular material consistent with mucopolysaccharides and lamellar concentric bodies consistent with phospholipids - are found on EM of conjunctival and corneal biopsy material. Mild hepatosplenomegaly may be present. Facial dysmorphism is not a prominent feature, but puffy eyelids and a coarse face have been reported (Chitayat et al., 1991). The facial features may also coarsen with age.

Schiffmann et al., (1998) studied 15 patients and found an increased chance of iron deficiency. Gastroscopy in three patients showed that parietal cells contained large lysosomal inclusions. Constitutive achlorhydria was demonstrated.

About 50% of cases have been of Ashkenazi Jewish descent, and the carrier frequency in this population is 1 in 100 (Bargal et al., 2000).

In a follow-up study of 28 patients by Altarescu et al., (2002) all had achlorhydria with an elevated plasma gastrin level, and 12 had iron deficiency anemia. Mutations in the MCOLN1 gene were present in all.

Smith et al., (2002) reviewed the ophthalmic findings in 22 patients. All patients demonstrated some degree of corneal clouding, retinal vascular attenuation and optic nerve pallor. Extraocular motility disturbance (strabismus and/or nystagmus) was reported in 63%.

Note the four patients reported by Bindu et al., (2009) from India, who presented with spasticity. None had corneal or retinal problems, although one had optic atrophy. All had thinning of the corpus callosum.

Wakabayashi et al., (2011) argue Mucolipidosis type IV is underrecognized due to its variable phenotypic presentation, and the disorder has been misdiagnosed as cerebral palsy.

Fisher et al., (2017) reported the longitudinal development of a child who participated in an augmentative and alternative communication intervention and showed improvement of expressive vocabulary.

Age of Onset:
The emergence of neurologic manifestations, such as severe psychomotor delay, is variable but usually starts in early childhood and typically in the first year of life. The onset of ophthalmologic symptoms, such as corneal clouding and retinal degeneration, also varies but is common during the first and second year of life.

Molecular genetics:
Slaugenhaupt et al., (1999) mapped the gene to 19p13.2-13.3. Bargal et al., (2000), Sun et al., (2000) and Bassi et al., (2000) demonstrated mutations in a novel gene encoding a protein of 580 amino acids named mucolipin-1. There appeared to be one transmembrane helix and at least five transmembrane domains. It was speculated that this was a new ion channel protein.

From haplotype analysis, Bassi et al., (2000) identified two major founder mutations in the Ashkenazi Jewish population.

A method of rapid detection for the two common Ashkenazi Jewish mutations - (IVS3-1A->G and delEX1-EX7) - is reported by Wang et al., (2001).

Gilbert (2001) reviewed the possibility of carrier screening in Ashkenazi Jewish populations.

Edelmann et al., (2002) reported their experience in screening for carrier status in the American Ashkenazi Jewish population. The frequencies of the IVS3-2A-G and 511del6434 mutations were 0.54% and 0.25%, respectively, for a combined carrier frequency of 0.79% or 1 in 27 individuals (95% CI 0.40%-1.17%). The addition of both mutations causing this neurodegenerative disorder should be considered for parental carrier screening in this population.

Shiihara et al., (2016) described a male patient with mild clinical presentation; no corneal clouding was present. White matter volume reduction over time was observed; additional features were cerebellar atrophy, low signal intensities in the globus pallidi and thalami, and features suggestive of iron accumulation.

A male patient from a consanguineous family was reported by Gowda et al., (2017).

Genotype-Phenotype Correlations:
The two common Ashkenazi Jewish mutations are associated with a more severe presentation of the disease (Altarescu et al., 2002).

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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