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Corneal Confocal Microscopy: A Novel Non-invasive Technique to Quantify Small Fibre Pathology in Peripheral Neuropathies
Published on: January 3, 2011
Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy
Georgia C Wright1, Richard Brown2, Hannah Grayton3
1University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Abstract:
Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.
Insights
Pathogenic variants in the FIG4 gene cause rare neurological disorders. This study identifies a novel phenotype in four children with a recurrent FIG4 variant, exhibiting features of both Charcot-Marie-Tooth disease type-4J and Yunis-Varón syndrome.
Area of Science:
- Genetics
- Neuroscience
- Cell Biology
Background:
- Pathogenic variants in the FIG4 gene, encoding a phosphatidylinositol-3,5-bisphosphatase, disrupt endocytic trafficking, leading to enlarged vesicle accumulation in neurons and fibroblasts.
- Bi-allelic pathogenic FIG4 variants are linked to neurological conditions like Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS).
Purpose of the Study:
- To characterize a novel clinical and radiological phenotype in four individuals from three families with a recurrent homozygous FIG4 missense variant (c.506A>C p.(Tyr169Ser)).
- To investigate the phenotypic variability associated with FIG4 missense variants and expand the diagnostic spectrum for FIG4-related disorders.
Main Methods:
- Clinical evaluation of four probands with detailed neurological examinations and family history.
- Nerve conduction studies (NCS) to assess peripheral neuropathy.
- Magnetic Resonance Imaging (MRI) to evaluate brain and spinal cord abnormalities.
Main Results:
- All four probands were homozygous for the recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser).
- The patients presented with a novel phenotype combining features of CMT4J and YVS, including infant-onset dystonia/hypotonia, distal muscle weakness, depressed reflexes, cognitive impairment, and swallowing difficulties.
- NCS revealed severe sensorimotor demyelinating peripheral neuropathy in two patients and intermediate/mildly reduced velocities in one.
- MRI demonstrated cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all affected individuals.
Conclusions:
- The study describes a novel clinicoradiological phenotype associated with a recurrent FIG4 missense variant, highlighting the phenotypic variability beyond previously defined diagnoses.
- FIG4 gene analysis is recommended for patients presenting with combined central and peripheral neurological signs and medullary radiological changes.
- Early diagnosis can inform reproductive choices and management strategies for individuals with FIG4-related disorders.
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