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Mucolipidosis IV: A milder form with
novel mutations and serial MRI
1Takashi SHIIHARA, 1Mio WATANABE, 1Kengo MORIYAMA, 2Yasuhiro
MARUYAMA, 3Atsuo KIKUCHI, 3Natsuko ARAI-ICHINOI, 3Mitsugu UEMATSU,
1Department of Neurology, Gunma Children’s Medical Center
2Department of Ophthalmology, Kiryu Kosei General Hospital
3Department of Pediatrics, Tohoku University School of Medicine
4Division of Medical Genetics, Gunma Children’s Medical Center
Conflict of Interest (COI) of the Principal Presenter：No potential COI to disclose
Conflict of Interest (COI) of the Co-Presenter：No potential COI to disclose
Mucolipidosis IV (MLIV) (OMIM #252650)
An autosomal recessive lysosomal storage disorder,
frequently found among Ashkenazi Jewish
Typically showing an intellectual disability, corneal
opacities, and delayed motor milestones during
infancy, with a relatively static course.
The causative gene, MCOLN1, identified in 2000.
No report from Japan, until 2015.
A 9-year-old Japanese boy, the second child from healthy, non-
consanguineous parents, with no family history of neurological illness.
Born at 38 weeks gestation, via a normal delivery, after an
uncomplicated pregnancy. His weight was 2,700 g (−0.8, SD); length,
48.0 cm (−0.5, SD); and occipito-frontal circumference (OFC), 31.0
cm (−1.6, SD).
His developmental milestones were as follows: head control at 5
months, sitting alone at 8 months, crawling at 1 year, and aided
walking at 2 years). Strabismus was noted at 4 months.
At 2 years 3 months, he was referred to our hospital. He showed
lower-extremity spasticity and microcephaly; his OFC was 44.4 cm
MRI at 2 years 6 months
Marked thinning of the corpus callosum
MRI at 2 years 6 months
Around 3 years
Thorough examinations, including chromosome
G-banding, lysosomal enzymes, amino acids,
organic acids, auditory brainstem responses,
peripheral nerve electrophysiology, and
cerebrospinal fluid analysis. All tests showed no
An ophthalmologic examination also revealed no
distinct abnormalities, except for slight paling in
both discs and intermittent exotropia.
At 4 years (pre-exome era)
Gene analyses for myelination-related
genes, such as, PLP1 (OMIM *300401),
GJA12 (OMIN *608803), and MBP
(OMIM *159430), were not revealing.
At 9 years (exome era)
MCOLN1 (OMIM *605248) mutations
Pathogenicity of the mutations
c.410T>C (p.Leu137Pro), in-silico analytical tools revealed
inconsistent predictions; benign to deleterious. However, the
substituted leucine residue (p.Leu137) was highly conserved
among the vertebrae.
c.802_803delAG (p.Ser268Trpfs*17), a frameshift, followed by a
premature stop codon. These mutations were likely to be
Serum gastrin level
Serum gastrin level was markedly
elevated: 5,300 (normal: 0−200) pg/ml.
Another unique common finding for
MLIV, which we knew after the exome
Marked thinning of
the corpus callosum
FLAIR high in the
T2 low in the
globus pallidi and
Common features of MLIV; psychomotor delays,
vision impairment, strabismus, corneal clouding,
white matter hyper-intensities on T2-weighted
images, a hypoplastic corpus callosum , cerebellar
atrophy, and elevated blood gastrin levels (which
our patient already had at 2-3 years old).
To make correct diagnosis for rare under-
recognized disorders, whole-exome sequencing is
powerful (we clinicians might feel somewhat
Take home message
If you see a patient with presumably genetic
white matter abnormalities and a thin corpus
callosum, you’d better see the patient's
eyes and a serum gastrin level.
Please refer our article below;
Brain Dev. 2016 Feb 26. pii: S0387-7604(16)00047-4. doi:
10.1016/j.braindev.2016.02.009. [Epub ahead of print]