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Mucolipidosis type IV(ML4)

MedGen UID:
68663
Concept ID:
C0238286
Disease or Syndrome
Synonyms: ML 4; ML IV; ML4; Mucolipidosis type 4
SNOMED CT: Mucolipidosis type IV (725296006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): MCOLN1 (19p13.2)
 
Monarch Initiative: MONDO:0009653
OMIM®: 252650
Orphanet: ORPHA578

Disease characteristics

Excerpted from the GeneReview: Mucolipidosis IV
Mucolipidosis IV (MLIV) is an ultra-rare lysosomal storage disorder characterized by severe psychomotor delay, progressive visual impairment, and achlorhydria. Individuals with MLIV typically present by the end of the first year of life with delayed developmental milestones (due to a developmental brain abnormality) and impaired vision (resulting from a combination of corneal clouding and retinal degeneration). By adolescence, all individuals with MLIV have severe visual impairment. A neurodegenerative component of MLIV has become more widely appreciated, with the majority of individuals demonstrating progressive spastic quadriparesis and loss of psychomotor skills starting in the second decade of life. About 5% of individuals have atypical MLIV, manifesting with less severe psychomotor impairment, but still exhibiting progressive retinal degeneration and achlorhydria. [from GeneReviews]
Authors:
Albert Misko  |  Yulia Grishchuk  |  Ehud Goldin, et. al.   view full author information

Additional descriptions

From OMIM
Mucolipidosis IV is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities. The lysosomal hydrolases in ML IV are normal, in contrast to most other storage diseases. The disorder results from a defect in transport along the lysosomal pathway, affecting membrane sorting and/or late steps of endocytosis, which causes intracellular accumulation of lysosomal substrates. Over 80% of the patients in whom the diagnosis of ML IV has been made are Ashkenazi Jews, including severely affected and mildly affected patients (Chen et al., 1998).  http://www.omim.org/entry/252650
From MedlinePlus Genetics
Mucolipidosis type IV is an inherited disorder characterized by delayed development and vision impairment that worsens over time. The severe form of the disorder is called typical mucolipidosis type IV, and the mild form is called atypical mucolipidosis type IV.

Approximately 95 percent of individuals with this condition have the severe form. People with typical mucolipidosis type IV have delayed development of mental and motor skills (psychomotor delay). Motor skills include sitting, standing, walking, grasping objects, and writing. Psychomotor delay is moderate to severe and usually becomes apparent during the first year of life. Affected individuals have intellectual disability, limited or absent speech, difficulty chewing and swallowing, weak muscle tone (hypotonia) that gradually turns into abnormal muscle stiffness (spasticity), and problems controlling hand movements. Most people with typical mucolipidosis type IV are unable to walk independently. In about 15 percent of affected individuals, the psychomotor problems worsen over time.

Vision may be normal at birth in people with typical mucolipidosis type IV, but it becomes increasingly impaired during the first decade of life. Individuals with this condition develop clouding of the clear covering of the eye (cornea) and progressive breakdown of the light-sensitive layer at the back of the eye (retina). By their early teens, affected individuals have severe vision loss or blindness.

People with typical mucolipidosis type IV also have impaired production of stomach acid (achlorhydria). Achlorhydria does not cause any symptoms in these individuals, but it does result in unusually high levels of gastrin in the blood. Gastrin is a hormone that regulates the production of stomach acid. Individuals with mucolipidosis type IV may not have enough iron in their blood, which can lead to a shortage of red blood cells (anemia). People with the severe form of this disorder usually survive to adulthood; however, they may have a shortened lifespan.

About 5 percent of affected individuals have atypical mucolipidosis type IV. These individuals usually have mild psychomotor delay and may develop the ability to walk. People with atypical mucolipidosis type IV tend to have milder eye abnormalities than those with the severe form of the disorder. Achlorhydria also may be present in mildly affected individuals.  https://medlineplus.gov/genetics/condition/mucolipidosis-type-iv

Clinical features

From HPO
Achlorhydria
MedGen UID:
1714
Concept ID:
C0001075
Pathologic Function
A condition in which production of hydrochloric acid in the stomach is absent.
Abnormal abdomen morphology
MedGen UID:
866551
Concept ID:
C4020869
Anatomical Abnormality
A structural abnormality of the abdomen ('belly'), that is, the part of the body between the pelvis and the thorax.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Photophobia
MedGen UID:
43220
Concept ID:
C0085636
Sign or Symptom
Excessive sensitivity to light with the sensation of discomfort or pain in the eyes due to exposure to bright light.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Dysplastic corpus callosum
MedGen UID:
98128
Concept ID:
C0431369
Congenital Abnormality
Dysplasia and dysgenesis of the corpus callosum are nonspecific descriptions that imply defective development of the corpus callosum. The term dysplasia is applied when the morphology of the corpus callosum is altered as a congenital trait. For instance, the corpus callosum may be hump-shaped, kinked, or a striped corpus callosum that lacks an anatomically distinct genu and splenium.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Developmental stagnation
MedGen UID:
341348
Concept ID:
C1848980
Finding
A cessation of the development of a child in the areas of motor skills, speech and language, cognitive skills, and social and/or emotional skills.
Progressive neurologic deterioration
MedGen UID:
381506
Concept ID:
C1854838
Finding
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Cerebral dysmyelination
MedGen UID:
343222
Concept ID:
C1854885
Finding
Defective structure and function of myelin sheaths of the white matter of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Ganglioside accumulation
MedGen UID:
1684843
Concept ID:
C5139036
Finding
Defects in the lysosomal glycosidases or specific co-activators, result in accumulation of the substrates, such as glycosphingolipids, including gangliosides in GM1 gangliosidosis (Tay-Sachs disease) and GM2 gangliosidosis (Sandhoff disease).
Hypergastrinemia
MedGen UID:
1674418
Concept ID:
C0853890
Finding
An elevated amount of gastrin in the blood.
Corneal opacity
MedGen UID:
40485
Concept ID:
C0010038
Finding
A reduction of corneal clarity.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Opacification of the corneal stroma
MedGen UID:
602191
Concept ID:
C0423250
Finding
Reduced transparency of the stroma of cornea.
Decreased light- and dark-adapted electroretinogram amplitude
MedGen UID:
326793
Concept ID:
C1839025
Finding
Descreased amplitude of eletrical response upon electroretinography.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Abnormality of mucopolysaccharide metabolism
MedGen UID:
869170
Concept ID:
C4023592
Finding
An abnormality of the metabolism of mucopolysaccharide.

Recent clinical studies

Etiology

Schiffmann R, Mayfield J, Swift C, Nestrasil I
Mol Genet Metab 2014 Feb;111(2):147-51. Epub 2013 Nov 21 doi: 10.1016/j.ymgme.2013.11.007. PMID: 24332805Free PMC Article
Bach G, Zeevi DA, Frumkin A, Kogot-Levin A
Biochem Soc Trans 2010 Dec;38(6):1432-5. doi: 10.1042/BST0381432. PMID: 21118102
Altarescu G, Sun M, Moore DF, Smith JA, Wiggs EA, Solomon BI, Patronas NJ, Frei KP, Gupta S, Kaneski CR, Quarrell OW, Slaugenhaupt SA, Goldin E, Schiffmann R
Neurology 2002 Aug 13;59(3):306-13. doi: 10.1212/wnl.59.3.306. PMID: 12182165
Smith JA, Chan CC, Goldin E, Schiffmann R
Ophthalmology 2002 Mar;109(3):588-94. doi: 10.1016/s0161-6420(01)00968-x. PMID: 11874766
Bach G
Mol Genet Metab 2001 Jul;73(3):197-203. doi: 10.1006/mgme.2001.3195. PMID: 11461186

Diagnosis

Boudewyn LC, Walkley SU
J Neurochem 2019 Mar;148(5):669-689. Epub 2018 Aug 30 doi: 10.1111/jnc.14462. PMID: 29770442Free PMC Article
Grimm C, Barthmes M, Wahl-Schott C
Handb Exp Pharmacol 2014;222:659-74. doi: 10.1007/978-3-642-54215-2_26. PMID: 24756725
Wakabayashi K, Gustafson AM, Sidransky E, Goldin E
Mol Genet Metab 2011 Nov;104(3):206-13. Epub 2011 Jun 16 doi: 10.1016/j.ymgme.2011.06.006. PMID: 21763169Free PMC Article
Smith JA, Chan CC, Goldin E, Schiffmann R
Ophthalmology 2002 Mar;109(3):588-94. doi: 10.1016/s0161-6420(01)00968-x. PMID: 11874766
Bach G
Mol Genet Metab 2001 Jul;73(3):197-203. doi: 10.1006/mgme.2001.3195. PMID: 11461186

Therapy

Schiffmann R, Mayfield J, Swift C, Nestrasil I
Mol Genet Metab 2014 Feb;111(2):147-51. Epub 2013 Nov 21 doi: 10.1016/j.ymgme.2013.11.007. PMID: 24332805Free PMC Article

Prognosis

Cuajungco MP, Silva J, Habibi A, Valadez JA
Pflugers Arch 2016 Feb;468(2):177-92. Epub 2015 Sep 4 doi: 10.1007/s00424-015-1732-2. PMID: 26336837Free PMC Article
Altarescu G, Sun M, Moore DF, Smith JA, Wiggs EA, Solomon BI, Patronas NJ, Frei KP, Gupta S, Kaneski CR, Quarrell OW, Slaugenhaupt SA, Goldin E, Schiffmann R
Neurology 2002 Aug 13;59(3):306-13. doi: 10.1212/wnl.59.3.306. PMID: 12182165
Slaugenhaupt SA
Curr Mol Med 2002 Aug;2(5):445-50. doi: 10.2174/1566524023362276. PMID: 12125810
Smith JA, Chan CC, Goldin E, Schiffmann R
Ophthalmology 2002 Mar;109(3):588-94. doi: 10.1016/s0161-6420(01)00968-x. PMID: 11874766
Amir N, Zlotogora J, Bach G
Pediatrics 1987 Jun;79(6):953-9. PMID: 2438637

Clinical prediction guides

Cougnoux A, Drummond RA, Fellmeth M, Navid F, Collar AL, Iben J, Kulkarni AB, Pickel J, Schiffmann R, Wassif CA, Cawley NX, Lionakis MS, Porter FD
J Neuroinflammation 2019 Dec 28;16(1):276. doi: 10.1186/s12974-019-1672-4. PMID: 31883529Free PMC Article
Chaer L, Harissi-Dagher M, Soucy JF, Ellezam B, Hamel P
J AAPOS 2018 Dec;22(6):469-471. Epub 2018 Aug 16 doi: 10.1016/j.jaapos.2018.04.011. PMID: 30120981
Vergarajauregui S, Connelly PS, Daniels MP, Puertollano R
Hum Mol Genet 2008 Sep 1;17(17):2723-37. Epub 2008 Jun 11 doi: 10.1093/hmg/ddn174. PMID: 18550655Free PMC Article
Slaugenhaupt SA
Curr Mol Med 2002 Aug;2(5):445-50. doi: 10.2174/1566524023362276. PMID: 12125810
Smith JA, Chan CC, Goldin E, Schiffmann R
Ophthalmology 2002 Mar;109(3):588-94. doi: 10.1016/s0161-6420(01)00968-x. PMID: 11874766

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    • ACMG ACT, 2011
      American College of Medical Genetics ACT Sheet, Carrier Screening ACT Sheet Ashkenazi Jewish Genetic Disorders

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