Childhood FIG4 Disorder Redefined as Neurodevelopmental-Neuromuscular Spectrum in 14 Patients

A rare genetic disorder long framed as a peripheral nerve disease looks strikingly different in childhood, according to an international study of 14 pediatric patients carrying biallelic variants in the FIG4 gene. The retrospective multicenter analysis, published in Annals of Clinical and Translational Neurology, found that the dominant clinical picture in affected children was not the classical neuropathy of Charcot–Marie–Tooth disease type 4J but a severe neurodevelopmental phenotype marked by global developmental delay, intellectual disability, and a high burden of movement disorders, particularly dystonia and bradykinesia. The authors argue that childhood FIG4 deficiency should be understood as a continuous neurodevelopmental-neuromuscular spectrum rather than a set of discrete clinical entities.

FIG4 encodes a phosphoinositide phosphatase on chromosome 6q21 that operates within a ternary complex alongside the scaffold protein VAC14 and the kinase PIKFYVE. Together these proteins regulate the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate, or PI(3,5)P2, a signaling lipid essential to intracellular vesicle trafficking and endolysosomal homeostasis. When FIG4 function is lost, PI(3,5)P2 levels fall, endolysosomes swell into enlarged vacuoles in neurons and Schwann cells, and progressive neurodegeneration follows in both the peripheral and central nervous systems. How severely cellular function is disrupted depends on the type and position of the mutation, which helps explain the heterogeneous phenotypes now attributed to this single gene.

The established genotype-phenotype map is intricate. Complete loss of protein function from biallelic null variants produces Yunis-Varón syndrome, a severe and often lethal disorder featuring cleidocranial dysplasia and global central nervous system involvement. Partial loss of function underlies CMT4J, most commonly arising from compound heterozygosity of the frequent p.Ile41Thr missense variant with a null allele; clinically it is a severe, early-onset motor and sensory neuropathy combining axonal loss and demyelination, sometimes mimicking acquired inflammatory neuropathies because conduction slowing is non-uniform and conduction blocks occur. A homozygous missense variant causing partial loss of function has also been linked to bilateral temporooccipital polymicrogyria in one large consanguineous Moroccan family, with temporal lobe epilepsy, psychiatric symptoms, and behavioral abnormalities. In adults, heterozygous FIG4 variants have been reported as risk factors for amyotrophic lateral sclerosis type 11, and recent studies describe adult combinations of CMT4J and parkinsonism, suggesting vulnerability in dopaminergic signaling pathway maintenance.

To chart the pediatric end of this spectrum, the researchers assembled their cohort through ESNEK, an email-based surveillance system for rare neurological disorders in childhood, and through preexisting international collaborations. Inclusion required biallelic FIG4 variants and neurological features; children with monoallelic variants, unspecified variants, or insufficient clinical data were excluded. Child neurologists with long-term experience in pediatric neuromuscular disease and movement disorders examined the patients during routine care, and data were collected with standardized case report forms using Human Phenotype Ontology terms to avoid semantic redundancy. The study received ethics approval from the Ethics Committee of the Medical Faculty of the University of Duisburg-Essen.

The 14 patients came from 11 unrelated families, including one family with affected twins and another with three affected brothers. Nine patients were male and five female. Age at onset ranged from birth to 9 years, with a median of 6 months, and there were no signs of antenatal onset such as reduced fetal movements, arthrogryposis multiplex congenita, or polyhydramnios in any patient. Age at diagnosis ranged from 3 months to 16 years, and age at last examination from 4 months to 18.2 years. Twelve patients were of European descent and two of Asian origin. Seven children carried compound heterozygous variants and seven homozygous variants, yet despite that high proportion of homozygosity only one family reported consanguinity.

The clinical findings were broad and heterogeneous. Global delay affected 10 patients, or 71.4 percent, with motor and speech delay equally represented, and fine and gross motor delay was reported in 9 patients. Absent speech was documented in 8 patients, all of them over two years old. Global developmental delay and intellectual disability were each identified in 7 patients, and developmental regression occurred in 6, underscoring a dynamic disease course in a substantial subset. Behavioral comorbidities were frequent: autism spectrum disorder in 4 patients, attention deficit hyperactivity disorder in 2, impaired emotional regulation in 3, and aggressive or impulsive behavior in 3. Neuromuscular involvement was equally prominent, with abnormal deep tendon reflexes in 10 patients, most commonly areflexia, muscle weakness and abnormal muscle tone in 10 each, and hypotonia predominating over hypertonia. Gait abnormalities were highly prevalent at 12 patients, and notably, nine patients could not walk independently at the time of data acquisition, although among the four who never learned to walk independently only one was older than three years.

Involuntary movements emerged as a key feature, present in half of the cohort. Dystonia was most common at 5 patients, followed by bradykinesia and gait ataxia in 3 each, with action tremor in 2 and parkinsonism, athetosis, and extrapyramidal dyskinesia in 1 patient each. Pyramidal signs, including hyperreflexia, a positive Babinski sign, and spasticity, were each reported in 3 patients. A progressive course was observed in 8 patients, predominantly slow in evolution, while 2 patients had a non-progressive course. Electrophysiological studies in 8 patients showed marked heterogeneity with overlapping demyelinating and axonal features: abnormal sensory nerve conduction velocities in 6, demyelinating motor and sensory neuropathy in 4 each, mixed demyelinating-axonal polyneuropathy in 4, and motor or sensory axonal neuropathy in 3 each. Brain MRI in 9 patients revealed structural abnormalities in only 2, characterized by T2 hyperintensities of the cerebral white matter involving the basal ganglia and/or thalamus, and none of the patients showed polymicrogyria or hypoplasia of the corpus callosum or cerebellar vermis. Additional systemic features included seizures in 2 patients, feeding difficulties in 5, scoliosis in 4, and dysmorphic facial features in 3, while no cardiac or respiratory involvement was observed.

Phenotypic stratification revealed three principal patterns: a neurodevelopmental-dominant phenotype in 8 patients, frequently accompanied by movement disorder; a classical CMT-like neuropathic phenotype in 2 patients; and a complex neurological phenotype in 3 patients combining severe neuropathy with movement disorder and additional features such as ophthalmoparesis and dysphagia. One patient could not be assessed because of his very young age. Genotype-phenotype correlations were distinct. The recurrent missense variant c.122T>C, or p.Ile41Thr, was the most frequent allele, identified in 7 of 14 patients irrespective of ethnic origin. Zygosity mattered: the two patients homozygous for p.Ile41Thr presented with milder phenotypes and slower progression, with one retaining the ability to run at 18 years of age and the other remaining ambulatory with support at 14. When p.Ile41Thr was combined with a large deletion of exons 2–23 or the p.Gly288Asp substitution, both individuals became full-time wheelchair users in early childhood, whereas a patient with p.Ile41Thr and p.Trp332Ser remained ambulatory at four years. Patients with variants other than p.Ile41Thr generally presented with earlier onset and more rapid progression, and a homozygous frameshift variant, c.21del, was found in three siblings, the oldest of whom lost ambulation by 8.5 years, required a full-time wheelchair by age 12, and had severe intellectual disability. Severe intellectual disability was exclusively observed in patients with homozygous truncating mutations or compound heterozygous variants associated with an overall severe disease course.

The authors propose a dosage-dependent model in which truncating FIG4 variants are generally associated with earlier onset and more severe disease than missense variants, supporting loss of function as a major determinant of clinical severity, but they caution that the spectrum cannot be fully explained by a simple missense-versus-truncating dichotomy. Compound heterozygotes with one missense and one presumed null allele showed intermediate phenotypes with substantial variability, suggesting that the biochemical properties of the second missense variant critically influence the clinical course, possibly through protein misfolding, residual enzymatic activity, and effects on complex assembly. A threshold model of residual enzyme activity may apply, in which minimal remaining function suffices for peripheral nerve maintenance but is inadequate for normal brain development, a concept the authors say requires comparative functional analyses in well-controlled cellular models. The findings also carry clinical implications: the authors recommend broadening diagnostic screening to infants and children with unexplained global developmental delay, hypotonia, and early-onset movement disorders even without overt neuropathic signs, actively monitoring extrapyramidal symptoms, evaluating the basal ganglia and thalamus in MRI protocols, establishing multidisciplinary care, and designing clinical trials with multi-domain outcome measures. Because preclinical studies have demonstrated the benefit of AAV-mediated FIG4 replacement in CMT4J mouse models, the authors suggest early therapeutic intervention may be particularly relevant in severe neurodevelopmental phenotypes, while noting that the retrospective design, modest sample size, and lack of standardized scales and uniform imaging or electrophysiological protocols constrain the interpretation of their findings.

Subject of Research: Genotype-phenotype correlations in pediatric FIG4-associated neurological disease

Article Title: Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients

Article References: Gangfuß, A., Gowda, V. K., Natera‐de Benito, D., Munot, P., Vanegas, M., Darling, A., Reutlinger, C., Carrera‐Garcia, L., Wunderlich, G., Kölbel, H., Stüve, B., Muhmann, D., Monfort Belenguer, L., Barca, D.-G., Reddy C, V. S., Srinivasan, V. M., Anguita, C. M., Jungbluth, H., Dafsari, H. S., … Roos, A. (2026). Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients. Annals of Clinical and Translational Neurology, Article acn3.70561. https://doi.org/10.1002/acn3.70561

Image Credits: AI Generated

DOI: 10.1002/acn3.70561

Keywords: FIG4, CMT4J, Yunis-Varón syndrome, neurodevelopmental delay, dystonia, bradykinesia, PI(3,5)P2, endolysosomal, pediatric neurology, genotype-phenotype correlation, movement disorders, peripheral neuropathy