Cerebral hypomyelination associated with biallelic variants of FIG4

Abstract

The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G>A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defectsHuman Mutation. 2019;40:619-630. wileyonlinelibrary.com/journal/humu Yes, moderate cognitive impairment Low-borderline IQ No speech at 4 year Limited communication Limited communication Limited communication (Continues) 626 |

Roles of PIKfyve in multiple cellular pathways

“…Defects in the PIKfyve complex are linked to human diseases, especially those of the nervous system [ 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ], although the underlying molecular mechanisms are not clear. For example, mutations in Fig4 predicted to have a modest effect in the regulation of PI(3,5) 2 are linked to Charcot-Marie-Tooth syndrome (CMT4J), a peripheral neuropathy, as well as some cases of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS).…”

VAC14 syndrome in two siblings with retinitis pigmentosa and neurodegeneration with brain iron accumulation

“…This can also include profound developmental delay, absent reflexes, persistent ophisthotonus, roving eye problems, severe feeding intolerance, skeletal abnormalities, heart defects, limb defects, cataracts, structural brain anomalies, and episodes of irritability (Lines et al 2017). A more recent study presented an additional four families with variants in FIG4, in which the ocular findings in each affected child in Family 4 were initially described as bull's eye maculopathy (Lenk et al 2019). The more severely affected sibling (Patient 6) was shown to have optic atrophy, retinal atrophy, and vascular attenuation.…”

Beyond PI3Ks: targeting phosphoinositide kinases in disease

“…Could chronic reductions in PI(3,5)P 2 levels via PIKfyve inhibition be a general treatment for neurodegenerative disease? As discussed above, loss of function of any member of the PIKfyve complex (PIKfyve-FIG4-VAC14) itself causes neurodegenerative phenotypes in mice as well as in humans, including ALS 35 , the peripheral neuropathy Charcot-Marie-Tooth disease 32,33 , and a severe neuropathy that includes hypo-myelination of central neurons 56 . Therefore, PIKfyve activity seems essential for central and peripheral nervous system homeostasis.…”