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Mucolipidosis IV: A milder form with
novel mutations and serial MRI
findings
1Takashi SHIIHARA, 1Mio WATANABE, 1Kengo MORI...
Mucolipidosis IV (MLIV) (OMIM #252650)
An autosomal recessive lysosomal storage disorder,
frequently found among Ashkenazi...
Case report
A 9-year-old Japanese boy, the second child from healthy, non-
consanguineous parents, with no family history ...
MRI at 2 years 6 months
Marked thinning of the corpus callosum
T1-weighted
mid-sagittal
MRI at 2 years 6 months
White matter
volume reduction
and signal
abnormalities (T2・
FLAIR>T1)
→ hypomyelination
or else?
T...
Around 3 years
Thorough examinations, including chromosome
G-banding, lysosomal enzymes, amino acids,
organic acids, audit...
At 4 years (pre-exome era)
Gene analyses for myelination-related
genes, such as, PLP1 (OMIM *300401),
GJA12 (OMIN *608803)...
At 9 years (exome era)
Compound heterozygous
MCOLN1 (OMIM *605248) mutations
Pathogenicity of the mutations
c.410T>C (p.Leu137Pro), in-silico analytical tools revealed
inconsistent predictions; benig...
Serum gastrin level
Serum gastrin level was markedly
elevated: 5,300 (normal: 0−200) pg/ml.
Another unique common finding ...
Serial MRI
Tanigawa-dake
Marked thinning of
the corpus callosum
FLAIR high in the
bilateral
periventricular
areas
Cerebellar atrophy
T2 low in the
...
Discussion
Common features of MLIV; psychomotor delays,
vision impairment, strabismus, corneal clouding,
white matter hype...
Take home message
If you see a patient with presumably genetic
white matter abnormalities and a thin corpus
callosum, you’...
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Mucolipidosis type4 case report

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A case report of Mucolipidosis type4

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Mucolipidosis type4 case report

  1. 1. Mucolipidosis IV: A milder form with novel mutations and serial MRI findings 1Takashi SHIIHARA, 1Mio WATANABE, 1Kengo MORIYAMA, 2Yasuhiro MARUYAMA, 3Atsuo KIKUCHI, 3Natsuko ARAI-ICHINOI, 3Mitsugu UEMATSU, 4Kiyoko SAMESHIMA 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
  2. 2. Mucolipidosis IV (MLIV) (OMIM #252650) An autosomal recessive lysosomal storage disorder, frequently found among Ashkenazi Jewish population. 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.
  3. 3. Case report 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 (−2.3, SD).
  4. 4. MRI at 2 years 6 months Marked thinning of the corpus callosum T1-weighted mid-sagittal
  5. 5. MRI at 2 years 6 months White matter volume reduction and signal abnormalities (T2・ FLAIR>T1) → hypomyelination or else? T1 T2 Axial Axial FLAIR T2 Axial Coronal
  6. 6. 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 abnormalities. An ophthalmologic examination also revealed no distinct abnormalities, except for slight paling in both discs and intermittent exotropia.
  7. 7. 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.
  8. 8. At 9 years (exome era) Compound heterozygous MCOLN1 (OMIM *605248) mutations
  9. 9. 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 pathogenic.
  10. 10. 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 result.
  11. 11. Serial MRI Tanigawa-dake
  12. 12. Marked thinning of the corpus callosum FLAIR high in the bilateral periventricular areas Cerebellar atrophy T2 low in the globus pallidi and thalami, suggesting iron accumulation Appeared Later
  13. 13. Discussion 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 powerless).
  14. 14. 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]

A case report of Mucolipidosis type4

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