Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy

Clin Genet. 2020 Aug;98(2):147-154. doi: 10.1111/cge.13771. Epub 2020 Jun 10.

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.

Keywords: FIG4; hereditary sensory and motor neuropathy; intellectual disability; olivary nucleus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Charcot-Marie-Tooth Disease / complications
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • Child
  • Child, Preschool
  • Cleidocranial Dysplasia / complications
  • Cleidocranial Dysplasia / genetics*
  • Cleidocranial Dysplasia / pathology
  • Dystonia / complications
  • Dystonia / genetics
  • Dystonia / pathology
  • Ectodermal Dysplasia / complications
  • Ectodermal Dysplasia / genetics*
  • Ectodermal Dysplasia / pathology
  • Female
  • Flavoproteins / genetics*
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Limb Deformities, Congenital / complications
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / pathology
  • Male
  • Micrognathism / complications
  • Micrognathism / genetics*
  • Micrognathism / pathology
  • Muscle Hypotonia / complications
  • Muscle Hypotonia / genetics
  • Muscle Hypotonia / pathology
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • Phosphoric Monoester Hydrolases / genetics*

Substances

  • Flavoproteins
  • FIG4 protein, human
  • Phosphoric Monoester Hydrolases

Supplementary concepts

  • Yunis Varon syndrome