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FIG4
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FIG4

FIG4 (FYVE Domain Containing 4) is a gene that encodes a lipid phosphatase crucial for maintaining lysosomal function and regulating intracellular vesicle trafficking. 

Mutations in FIG4 disrupt these processes, contributing to a range of neurological disorders, including Charcot-Marie-Tooth disease type 4J, Yunis-Varon syndrome, and some forms of epilepsy and ALS.

What is FIG4 (FYVE Domain Containing 4)?

The FIG4 gene encodes a phosphoinositide 5-phosphatase enzyme that plays a key role in regulating vesicle trafficking within cells. 

Though originally classified as a phosphatase, FIG4 has both enzymatic and non-enzymatic functions. It is critically involved in maintaining lysosomal membrane integrity and proper intracellular transport of organelles, particularly in neurons and muscle cells.

Clinically, this gene is important because its loss of function results in vacuole accumulation and lysosomal enlargement, contributing to the pathogenesis of several inherited neurological disorders.

FIG4: A Phosphatase Involved in Endosomal Trafficking

Enzymatic Role: Regulates levels of PI(3,5)P₂, a lipid required for vesicle trafficking and lysosome function, by dephosphorylating it to PI(3)P.

Scaffolding Role: Works in a complex with VAC14 (scaffold protein) and FAB1/PIKFYVE (kinase). This complex is essential for PI(3,5)P₂ synthesis and lysosomal membrane regulation.

Phosphatase-Independent Activity: FIG4's ability to maintain lysosomal size does not require enzymatic activity. A catalytically inactive FIG4 mutant (C450S) can still rescue lysosomal defects, indicating a structural role is central.

FIG4 Mutations and Associated Disorders

Mutations in FIG4 are implicated in a growing list of neurological and developmental disorders. 

Charcot-Marie-Tooth disease type 4J (CMT4J)

Charcot-Marie-Tooth Disease (CMT) is a group of inherited disorders that damage the peripheral nerves. This leads to progressive muscle weakness—typically starting in the feet and legs—and decreased sensation. 

Common signs include high arches, curled toes, and difficulty walking. 

Symptoms vary in severity and often begin in adolescence or early adulthood. CMT is caused by mutations in genes that affect nerve structure or function, with different types inherited in autosomal dominant, recessive, or X-linked patterns. 

While it rarely shortens lifespan, it can cause significant disability. Genetic testing can confirm the diagnosis and support family planning.

Charcot-Marie-Tooth disease type 4J (CMT4J) is a rare inherited subtype of this disorder caused by two faulty copies of the FIG4 gene—usually one missing and one with a partial mutation. It leads to progressive muscle weakness, sensory loss, and sometimes scoliosis, often starting in childhood. 

This form of CMT disease occurs because FIG4 helps keep lysosomes—the cell’s cleanup centers—working properly. When FIG4 doesn't function, waste builds up in nerve cells, causing damage and loss of function over time.

Yunis-Varon syndrome (YVS)

Another severe condition linked to FIG4 is Yunis-Varon syndrome (YVS): in contrast to CMT4J, which is caused by partial loss of FIG4 function, YVS is caused by complete functional loss

YVS presents with skeletal abnormalities, intellectual disability, dilated cardiomyopathy, and widespread vacuolization in muscle and cartilage tissues.

Familial Epilepsy with Polymicrogyria

Mutations in the FIG4 gene have been linked to a rare form of epilepsy associated with polymicrogyria—a condition where the brain develops too many small folds. 

In a Moroccan family with multiple affected members, researchers identified a homozygous FIG4 mutation (p.Asp783Val) that caused seizures, psychiatric symptoms, and structural brain abnormalities, particularly in the temporo-occipital regions. Functional studies in mice confirmed that this mutation leads to a partial loss of FIG4 function, impairing normal brain development and endosomal trafficking. 

While FIG4 mutations are already known to cause Charcot-Marie-Tooth disease type 4J (CMT4J) and Yunis-Varón syndrome, this study expands the clinical spectrum to include cortical malformations, seizures, and psychiatric issues. 

Amyotrophic Lateral Sclerosis Type 11 (ALS11)

Amyotrophic lateral sclerosis type 11 (ALS11) is linked to mutations in the FIG4 gene, which codes for a lipid involved in vesicle trafficking. 

While FIG4 mutations are known to cause CMT4J, one study found rare FIG4 variants in about 2% of ALS and Primary Lateral Sclerosis (PLS) patients.

While ALS due to FIG4 mutations can show a variable presentation, clinical features of ALS11 include:

  • Late adult onset (average ~56 years)
  • Prominent corticospinal signs
  • Normal nerve conduction studies
  • No sensory loss or dementia

Unlike CMT4J, which affects sensory nerves and Schwann cells, ALS11 is a motor neuron disease with normal conduction velocity. FIG4 mutations may act through partial loss of function or dominant-negative effects.

Who Should Get FIG4 Genetic Testing?

FIG4 genetic testing is most appropriate for individuals showing clinical features consistent with CMT4J or Yunis-Varon Syndrome (YVS). 

CMT4J

For CMT4J, testing should be considered in patients with early-onset, progressive distal muscle weakness, sensory loss, and features like scoliosis. 

YVS

For YVS, individuals presenting with skeletal abnormalities, intellectual disability, and developmental delays—particularly if multiple systems are involved—should be evaluated for FIG4 mutations. 

Family Members of Affected Individuals

Family members of individuals diagnosed with CMT4J or YVS may also consider carrier testing or risk assessment during family planning. 

Patients with Motor Neuron Disease

Additionally, testing may be warranted in patients with motor neuron disease who lack mutations in more common ALS-related genes, especially those with atypical features such as slow disease progression, predominant upper motor neuron (UMN) signs, or coexisting sensory symptoms. 

Genetic counseling is highly recommended both before and after testing to help interpret results and discuss inheritance and clinical implications.

What Do Specific FIG4 Mutations Mean?

Pathogenic FIG4 mutations support the diagnosis of related disorders. 

In CMT4J and YVS, they usually follow an autosomal recessive pattern and cause partial or complete loss of function. For example, I41T reduces FIG4 stability, while L17P disrupts its structural role. 

In ALS, FIG4 mutations are typically heterozygous. Residual FIG4 activity appears to influence disease severity and CNS involvement.

What Does the Absence of Pathogenic FIG4 Mutations Mean?

A negative FIG4 result doesn't rule out genetic causes of neuropathy or motor neuron disease. These conditions are genetically diverse. If suspicion remains, consider broader testing such as exome sequencing or targeted gene panels. 

Always interpret FIG4 results alongside clinical findings, family history, neuroimaging, and EMG studies.

Test Procedure and Interpretation

Testing for FIG4 is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for FIG4 genetic testing are considered to be without mutations that can alter the activity of the FIG4 proteins.

Clinical Implications of Positive FIG4 Mutations

The clinical implications of a positive FIG4 mutation test result will vary by individual, although FIG4 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of symptoms associated with CMT4J, YVS, or ALS11.

Patients or practitioners with questions about the clinical implications of FIG4 mutations should seek further assessment with a genetic counselor or expert. 

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See References

Amyotrophic lateral sclerosis: MedlinePlus Genetics. (2016, March 1). Medlineplus.gov. https://medlineplus.gov/genetics/condition/amyotrophic-lateral-sclerosis/

Baulac S, Lenk GM, Dufresnois B, Ouled Amar Bencheikh B, Couarch P, Renard J, Larson PA, Ferguson CJ, Noé E, Poirier K, Hubans C, Ferreira S, Guerrini R, Ouazzani R, El Hachimi KH, Meisler MH, Leguern E. Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology. 2014 Mar 25;82(12):1068-75. doi: 10.1212/WNL.0000000000000241. Epub 2014 Mar 5. PMID: 24598713; PMCID: PMC3962989.

Bharadwaj R, Cunningham KM, Zhang K, Lloyd TE. FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Hum Mol Genet. 2016 Feb 15;25(4):681-92. doi: 10.1093/hmg/ddv505. Epub 2015 Dec 11. PMID: 26662798; PMCID: PMC4743688.

Charcot-Marie-Tooth disease: MedlinePlus Genetics. (2018, October 1). Medlineplus.gov. https://medlineplus.gov/genetics/condition/charcot-marie-tooth-disease/

Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., Figlewicz, D., Brown, R. H., & Meisler, M. H. (2009). Deleterious Variants of FIG4, a Phosphoinositide Phosphatase, in Patients with ALS. The American Journal of Human Genetics, 84(1), 85–88. https://doi.org/10.1016/j.ajhg.2008.12.010

Johns Hopkins Medicine. (n.d.). Charcot-Marie-Tooth Disease. Www.hopkinsmedicine.org. https://www.hopkinsmedicine.org/health/conditions-and-diseases/charcotmarietooth-disease

Liu, C.-Y., Lin, J.-L., Feng, S.-Y., Che, C.-H., Huang, H.-P., & Zou, Z.-Y. (2022). Novel Variants in the FIG4 Gene Associated With Chinese Sporadic Amyotrophic Lateral Sclerosis With Slow Progression. Journal of Clinical Neurology, 18(1), 41–41. https://doi.org/10.3988/jcn.2022.18.1.41

Orengo JP, Khemani P, Day JW, Li J, Siskind CE. Charcot Marie Tooth disease type 4J with complex central nervous system features. Ann Clin Transl Neurol. 2018 Jan 22;5(2):222-225. doi: 10.1002/acn3.525. PMID: 29468183; PMCID: PMC5817837.

Osmanovic, A., Rangnau, I., Kosfeld, A. et al. FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study. Eur J Hum Genet 25, 324–331 (2017). https://doi.org/10.1038/ejhg.2016.186

Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain. 2008 Aug;131(Pt 8):1990-2001. doi: 10.1093/brain/awn114. Epub 2008 Jun 12. PMID: 18556664; PMCID: PMC2724900.

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