Case report and literature review: Novel compound heterozygous FIG4 variants causing both of peripheral and central nervous system defects

Abstract

Background: Pathogenic variants in the FIG4 gene have been described to be associated with a diverse spectrum of syndromes, such as autosomal recessive bilateral temporooccipital polymicrogyria (OMIM 612691), autosomal dominant amyotrophic lateral sclerosis-11 (ALS11; OMIM 612577), autosomal recessive Charcot-Marie-Tooth disease, type 4J (CMT4J; OMIM 611228), and autosomal recessive Yunis-Varon syndrome (YVS; OMIM 216340). Heterozygous FIG4 variants are responsible for ALS11 characterized by progressive muscular weakness, atrophy, and bulbar palsy. CMT4J is a disorder of peripheral nervous system defects mainly presenting with a highly variable onset of proximal and/or distal muscle weakness. YVS is a disorder of severe neurological involvement with central nervous system (CNS) dysfunction and extensive skeletal anomalies.

Case presentation: We reported two Chinese siblings born with a weakness in all limbs. They experienced rapidly progressive weakness in distal limbs. At the age of 6 years, the elder brother presented with severe scoliosis and cervical kyphosis. They both had global developmental delay and a CNS involvement with cognitive deficits and swallowing problems. Genetic screening in the patients' family for inherited diseases was recommended. Novel compound heterozygous variants in the FIG4 gene (c.2148delTinsAA and c.317A > G) were found by whole-exome sequencing in the patients. These variants were confirmed by Sanger sequencing in family members.

Conclusions: Herein, we reported two Chinese male patients with CMT4J who presented with abnormal CNS features. CMT4J with CNS involvement has been very rarely reported. We hoped this study could expand the phenotypic and genetic spectrum of FIG4-related diseases. And we helped physicians to understand the genotype-phenotype correlation.

Keywords: Charcot-Marie-Tooth disease; FIG4 gene; central nervous system; cognitive deficits; compound heterozygous variants.

Figure 1

Pedigree chart and Sanger sequencing results of the family members. The proband was the younger brother (marked with the black arrow). The two siblings carried the compound heterozygous FIG4 variants. The results of Sanger sequencing indicated that the father was a heterozygous carrier of the c.2148delTinsAA (p.P718Tfs*3) variant (marked with the black box), and the mother was a heterozygous carrier of the c.317A > G (p.Y106C) variant (marked with the red arrow).

Figure 2

Upper and lower limbs of the two siblings. (A) The proband (1 year old); (B) the elder brother (7 years old).

Figure 3

Brain MRI of the proband. Brain MRI showed the normal bilateral lateral ventricle and slightly thinner corpus callosum.

Figure 4

The spine x-rays. (A) The spine x-rays of the proband; (B) the spine x-rays of the elder brother. The spine x-rays showed that the spine of the proband was normal and the elder brother had severe scoliosis and cervical kyphosis.

Figure 5

Prediction of interactomic interactions of the wild-type and mutant site (Y106 residue mapped to Y94 in the PDB structure). Residues in the wild-type and mutant sites were colored in light green and shown as sticks. The respective chemical interactions were labeled as dotted lines and colored as follows: hydrogen bonds—(red), weak hydrogen bonds—(orange), hydrophobic contacts—(green), amide-amide contacts—(blue), and ionic interactions—(gold). Amino acid residues were also colored according to type, namely nitrogen (blue), oxygen (red), and sulfur (yellow). In comparison to the wild-type site, some interactions (hydrophobic contacts, amide-amide contact, and ionic interactions) were observed to be lost in the mutant site.

Figure 6

The transition between PtdIns(3,5)P2 and PtdIns3P. FIG4 catalyzes the dephosphorylation of PtdIns(3,5)P2 to form PtdIns3P. PIKFYVE complex consists of three subunits (PIKFYVE, VAC14, FIG4). PIKFYVE is the sole enzyme that catalyzes the phosphorylation of PtdIns3P on the fifth hydroxyl of the myo-inositol ring to form PtdIns(3,5)P2.