Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV—A Review and Case Series
Abstract
:1. Introduction
1.1. The Mucolipin (TRPML) Subfamily
1.2. Ethnicity
2. Clinical Manifestations
2.1. Dysmorphic Features
2.2. Neurological Findings
2.3. Myopathy
2.4. Secondary Mitochondrial Dysfunction
2.5. Brain Neuroimaging
2.6. Sleep Disturbance
2.7. Ocular Findings
2.8. Achlorydia
2.9. Skin
2.10. Other Laboratory and Significant Clinical Findings
3. Discussion
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Ethical Issues
References
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---|---|---|---|---|---|
Riedel et al. 1985 [37] | 23-year-old male and his brother | N/A | conjunctival biopsy: membrane-bound vacuoles filled with fibrillogranular material and concentric membranous lamellar bodies indicating both storage of mucopolysaccharides and complex lipids | N/A | no corneal opacities until teens age; facial dysmorphism (described in the text) |
Amir et al. 1987 [34] | 20 Ashkenazic Jewish patients (10F/10M) aged 2–17 years | N/A | typical inclusion organelles on electron microscopy of conjunctival biopsy and/or skin biopsy tissue. The diagnosis was confirmed by demonstrating abnormal gangliosides storage in cultured fibroblasts. | N/A | developmental delay, corneal clouding, language function reduced |
Chitayat et al. 1991 [35] | 5 patients aged 20 months to 32 years | N/A | skin and conjunctival biopsies | N/A | minor congenital anomalies and facial dysmorphism (1 case, described in the text); puffy eyelids (5 cases), ptosis; coarsening of the facial appearance; myopathic face, a decline in facial movement; delayed onset puberty and no associated growth spurt (1 case) |
Casteels et al. 1992 [42] | 16 years old girl | N/A | conjunctival biopsy | N/A | ophthalmological findings as the only features |
Reis et al. 1993 [43] | 16 years old girl | N/A | conjunctival biopsy | N/A | minor motor difficulties; mild psychological disturbances |
Altarescu et al. 2002 [33] | 28 patients (age range 2 to 25), age at diagnosis 1 to 14 years | 1507 pg/mL (range 400 to 4100 pg/mL, normal 0 to 200 pg/mL) | skin or conjunctival biopsies and in cultured skin fibroblasts | c.[406-2A>G];[406-2A>G] p.?/p.? 9 pts | independent, ataxic, spasticity, reduced tone gait, modified pincer grasp (patient no 15); severe visual impairment as the only feature (patient no 13) |
c.[-1015_789del];[406-2A>G] p.0/p.? 8 pts | |||||
c.[-1015_789del];[-1015_789del] p.0/p.0 | |||||
c.[304C>T];[1084G>T] p.(Arg102*)/p.(Asp362Tyr) | |||||
c.[406-2A>G];[1222_1224del] p.?/p.(Phe408del) | |||||
c.[1406A>G];[1406A>G] p.?/p.? | |||||
c.[-1015_789del];[473_474del] p.0/p.(Thr158Lysfs*25) | |||||
c.1406A>G];[514C>T] p.?/p.(Arg172*) | |||||
c.[1084G>T];[?] b p.(Asp362Tyr)/p.0 | |||||
c.[1453_1463dup];[1453_1463dup] p.(Ser488Argfs*96)/p.(Ser488Argfs*96) | |||||
c.[317T>C];[1340T>C] p.(Leu106Pro)/p.(Leu447Pro) | |||||
Bindu et al. 2008 [36] | 4 cases; aged 14 (2), 16 and 18 years | N/A | electron microscopic studies of biopsy specimens from skin, conjunctiva, peripheral nerve, muscle and liver | no corneal abnormalities in all, optic atrophy in 1 patient; slowly progressive spastic paraparesis from the second decade of life (3 patients) and early childhood (1 patient); thin corpus callosum; intellectual disability (3 out of 4 patients); diagnosis of non-compressive myelopathy (1 case) (atypical presentation) | |
Tuysuz et al. 2009 [44] | Turkish patient | hypergastrinemia, iron deficiency anemia, | N/A | c.[1367C>T];[1367C>T] p.(Ser456Leu)/p.(Ser456Leu) | defects in the posterior limb of the internal capsule by MRI, cerebellar atrophy, micrognathia, and clinodactyly of the fifth fingers; spastic tetraplegia |
Geer at al. 2010 [45] | 4.5-year-old girl non-Jewish 11-year-old non-Jewish girl | 710 pg/mL (0–99 pg/mL) 526 pg/mL (0–99 pg/mL) | skin biopsy: vacuoles containing granular material and lipids compatible with a lysosomal storage disease. | c.[236_237ins93];[694A>C] p.0?/p.(Thr232Pro) | developmental delay, hypotonia, language delays hypotonia, limb spasticity, severe hypoplasia of the corpus callosum |
Mirabelli- Badenier et al. 2014 [46] | 5-year old Italian male | 191.26 pmol/L (11–54 pmol/L) | c.[395_397del;468_474dup]; [395_397del;468_474dup] p.?/p.? c | postnatal growth deficiency, non-progressive psychomotor delay and spasticity at onset in infancy | |
Chaer et al. 2018 [38] | 4-month-old French Canadian boy diagnosed at 2 | 726 ng/L (0–90 ng/L) | electron microscopy of skin biopsy: secondary lysosomes filled with concentric lamellar structures in the cytoplasm of eccrine duct cells and, to a lower extent, of endothelial cells | c.[694A>C];[785T>C] (p.Thr232Pro)/(p.Phe262Ser) | congenital anomalies and facial dysmorphism; hypoplastic optic nerves and a delayed P100 wave on visual evoked potentials. |
Case 1 | 20 years Pakistani old female | 157 pmol/L (<40 pmol/L) | N/A | c.[1256G>C];[1256G>C] p.(Arg419Pro)/p.(Arg419Pro) | GI: deranged liver function tests (ALT 123 U/L, ALP 1078 U/L), USS liver normal, fibroscan TE of 8 to 9 EkPa; gall bladder polyp; Eye: corneal clouding, cataracts, optic atrophy, retinal pigmentation; MRI head: subtle high signal in the periventricular deep white matter, the globus pallidus and thalamus signal slightly lower than in the rest of the basal ganglia on T2 sequences, suggestive of a relative increase in iron deposition; Hearing: sensorineural hearing loss, Other: severe learning disability, microcephaly, premature ovarian failure; recurrent periods of depression and anorexia |
Case 2 | 23-year-old Pakistani female | 179 pmol/L (<40 pmol/L) | N/A | c.[1256G>C];[1256G>C] p.(Arg419Pro)/p.(Arg419Pro) | GI: iron deficiency anemia at presentation; Developmental delay, severe learning disability; Eye: corneal clouding, optic nerve atrophy, retinitis pigmentosa, registered blind; MRI: small corpus callosum, but pituitary gland was unremarkable; Hearing: Sensorineural hearing loss Lost the ability to speak at the age of 8–10 year; CK 1400 U/L: congenital myopathy; premature ovarian insufficiency; MRI leg: osteofibrous dysplasia and adamantinoma |
Case 3 | 27-year-old Pakistani male | 198 pmol/L (<40 pmol/L) | N/A | c.[1256G>C];[1256G>C] p.(Arg419Pro)/p.(Arg419Pro) | GI: constipation, iron deficiency anemia; Eye: corneal clouding, retinitis pigmentosa, deterioration of his vision since the age of 5, nystagmus, exotropia, anterior and posterior subcapsular cataracts; Hearing: sensorineural hearing loss; Myopathy CK 3100 U/L; MRI: atrophic corpus callosum, microcephaly, deep white matter T2 signal abnormalities and hypointense thalami; Lost ability to communicate at the age of 15; Depression, gynecomastia |
Pathway | Diagnostic Clues |
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primary clinical manifestations, sequence of symptoms |
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diagnostic work-up |
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molecular testing and family counselling |
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follow-up |
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treatment |
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Jezela-Stanek, A.; Ciara, E.; Stepien, K.M. Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV—A Review and Case Series. Int. J. Mol. Sci. 2020, 21, 4564. https://doi.org/10.3390/ijms21124564
Jezela-Stanek A, Ciara E, Stepien KM. Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV—A Review and Case Series. International Journal of Molecular Sciences. 2020; 21(12):4564. https://doi.org/10.3390/ijms21124564
Chicago/Turabian StyleJezela-Stanek, Aleksandra, Elżbieta Ciara, and Karolina M. Stepien. 2020. "Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV—A Review and Case Series" International Journal of Molecular Sciences 21, no. 12: 4564. https://doi.org/10.3390/ijms21124564
APA StyleJezela-Stanek, A., Ciara, E., & Stepien, K. M. (2020). Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV—A Review and Case Series. International Journal of Molecular Sciences, 21(12), 4564. https://doi.org/10.3390/ijms21124564