Biallelic variants in the FIG4 gene cause Charcot-Marie-Tooth type 4J (CMT4J) and Yunis-Varon syndrome. There is increasing evidence of phenotypic overlap between CMT4J and Yunis-Varon syndrome, which presents with peripheral neuropathy and central nervous system (CNS) abnormalities, particularly parkinsonism. We aim to extend and specify the phenotype-genotype correlation of the FIG4 variants by presenting four cases of CMT4J, including two with parkinsonism. All patients carried the pathogenic FIG4 variant c.122T > C p.(Ile41Thr) in compound heterozygosity with another variant: c.793C > T p.(Arg265∗), c.498-1G > A, or c.447-2A > C. Disease onset occurred in the first or second decade of life. All presented with demyelinating sensorimotor polyneuropathy, distal muscle weakness of the upper and lower limbs, and foot deformity. In one patient, the muscle weakness was asymmetrical. Two patients developed parkinsonism. Our findings expand the phenotypic spectrum of FIG4-related disorders, reinforcing the link between CMT4J and parkinsonism. These insights are crucial for improving genetic diagnosis and advancing potential therapeutic strategies.

Yunis-Varón syndrome (YVS) is a severe autosomal recessive syndrome caused by mutations in the FIG4 gene. It is characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and a poor prognosis due to neurological and cardiovascular involvement. In this study, we observed a Chinese family with three patients presenting thumb and hallux dysplasia. Whole-genome sequencing (WGS) identified a compound heterozygous variant in the proband: c.2097-809A>G and c.1141C>T (p.R381*). The c.2097-809A>G variant generated an aberrant splicing transcript containing a pseudoexon from intron 18, as demonstrated by further RT-PCR and splicing analysis. This is the first deep intronic variant reported in the FIG4 gene. In addition, we provided prenatal diagnoses for the family. This study expands the genetic variant spectrum, provides additional molecular and clinical information, and broadens our understanding of the molecular mechanisms involved in the disease course.

Degeneration of peripheral motor and sensory axons is a key aspect of the pathophysiology of Charcot-Marie-Tooth disease and related inherited neurodegenerative conditions. Given that mutations in many (> 100) genes can cause these disorders, it is unclear if a generalized therapeutic strategy can be identified that will apply across these disease subtypes; however, strategies to prevent or slow axon degeneration are attractive candidates. Wallerian axon degeneration is an active process following insults such as nerve injury, and SARM1 is a central mediator of this process. When SARM1 is inhibited, axons distal to the site of injury persist for weeks rather than degenerating. In addition, SARM1 inhibition or genetic deletion has been shown to provide benefit in acquired neuropathies such as diabetic/metabolic neuropathy and chemotherapy-induced neuropathy in animal models. Here we examined the effects of genetically deleting Sarm1 in mouse models of CMT. We bred knockout mice lacking Sarm1 to three different mouse models of CMT or related disorders. These include mice lacking Gjb1, modeling CMT1X, mice with mutations in Kif1a, modeling hereditary sensory neuropathy IIC and spastic paraplegia type 30, and mice lacking Fig4, modeling CMT4J and Yunis-Varon syndrome. Clinically relevant outcomes measures including survival (Kif1a and Fig4), grip strength and motor behavior, peripheral neurophysiology, molecular biomarkers, and nerve histopathology were assessed for each model with and without Sarm1 expression. No improvement in the mutant phenotype was found for any model, although elevated levels of circulating neurofilament light chain levels were delayed in the Fig4 mice. Kif1a mice showed deficits slightly earlier in the absence of Sarm1. While we found no benefit from deleting Sarm1 in these mouse models, they were chosen for their human disease relevance and not for biochemical indicators that SARM1 may be a good target. Thus, SARM1 inhibition may still be effective in other forms of inherited neuropathy, but additional research will be required to identify those candidate subtypes.

Biallelic variants in FIG4 or VAC14 are associated with Yunis-Varón syndrome (YVS), which is characterized by multisystem involvement including skeletal findings, craniofacial dysmorphisms and central nervous system anomalies. Pathogenic variants in those same genes have also been associated with a predominantly neurological phenotype and with nonsyndromic conditions, such as Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. By describing 5 new cases of FIG4-associated YVS and reviewing the literature, we better delineate the clinical phenotype associated with loss of function of those genes. We also explore osteopenia mechanisms by assessing bone physiologic parameters in a mouse model. Exome sequencing or Sanger sequencing was performed in 5 unrelated individuals. Bone histomorphometry was performed in Fig4 plt/plt mice and compared with wild type. Relevant literature from the last 10 years was reviewed. All individuals presented a phenotype overlapping the typical YVS and the brain anomalies and neurologic syndrome. Clinical features included developmental delay, structural brain malformations, and skeletal anomalies, such as osteopenia. Biallelic FIG4 variants were identified in each individual. In mice, bone histomorphometry parameters suggested that osteopenia might be secondary to reduced bone formation rather than increased bone degradation. This study contributes to a better understanding of the phenotypic variability caused by pathogenic variants in FIG4 or VAC14 and suggests an important overlap between previously described phenotypes. The brain anomalies and neurologic syndrome is likely in the same spectrum as classical YVS. Further studies are still needed to clarify the effects of partial loss-of-function (hypomorphic) variants and to identify genotype-phenotype correlations.

Background/Objectives: The genetic underpinnings of Parkinson's disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Varón syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.