FIG4 Research Articles

Clinical and genetic features of patients suffering from CMT4J.

Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Charcot-Marie-Tooth 4J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations.

A review on yunis-varon syndrome

Yunis Varon Syndrome was first discovered by Emilio Yunis and Humberto Varon in the year 1980. It affects both genders in equal number. Most of the infants are with Cleidocranial dysplasia, ectodermal anomalities, distal aphalangia. By the characteristic features which including deformity of the pelvis, dislocation of hips , bone fracture, urinary tract abnormalities, central nervous system abnormalities by this they have reported the condition as Yunis Varon Syndrome.
 This is an autosomal recessive inherited multisystem disorder due to FIG4 gene mutations, consanguineous marriages, Lysosomal defects, which may leads to improper in the functioning of organs in the infants. Metabolic disorders in which abnormal growth due to some toxic substances in the body. Affected people with this syndrome may experience breathing problems, abnormalities in the skeletal system, congenital heart defects.
 Genetic testing for mutation can be detected through diagnosis. In some conditions they may also be detected before birth of the baby that is prenatally by ultrasonography.Many of the infants did not survive beyond on year. Genetic counselling will be of benefit for affected individuals and their families.

Case report: A variant of the FIG4 gene with rapidly progressive amyotrophic lateral sclerosis

Heterozygous autosomal-dominant FIG4 mutations are associated with amyotrophic lateral sclerosis (ALS). Here, we describe a variant of the FIG4 gene (c.350dupC, p.Asp118GlyfsTer9) in a patient with rapidly progressive ALS that has not previously been reported in ALS or primary lateral sclerosis (PLS) patients before. Our study provides further information on the genotypes and phenotypes of patients with FIG4 mutations.

STARTED FROM THE BOTTOM, NOW WE'RE HERE: THE UNRELENTING CASE OF CHARCOT MARIE TOOTH DISEASE FROM ANKLE WEAKNESS, TO VENOUS THROMBOEMBOLI, TO VENTILATOR DEPENDENCE

TYPE: Case Report TOPIC: Genetic and Developmental Disorders INTRODUCTION: Charcot Marie Tooth Disease Type 4J (CMT4J) is a rare inherited peripheral neuropathy caused by mutations of the lipid phosphatase FIG4 gene. Severe forms may lead to respiratory dysfunction. CASE PRESENTATION: A 44 year old male had an initial complaint of falls due to bilateral foot drop. Nerve conduction studies demonstrated axonal and demyelinating polyneuropathy. This raised suspicion for chronic inflammatory demyelinating polyneuropathy. He was started on intravenous immunoglobulin treatments and corticosteroids with no improvement, and soon he became wheelchair bound. 3 months after initial presentation, he developed shortness of breath and chest pain; he was diagnosed with provoked bilateral pulmonary emboli with pulmonary infarcts and started on rivaroxaban. Pulmonary function testing revealed severe restrictive lung disease with decreased respiratory muscle force necessitating a non-invasive auto-titration ventilation device (AVAPS-AE). Genetic testing performed at 4 months since initial symptoms revealed a heterozygous missense variant in the FIG4 gene consistent with CMT4J. 6 months after initial presentation, he went into cardiac arrest due to hypercapnic respiratory failure; return of spontaneous circulation was achieved, and eventually he underwent a tracheostomy and became ventilator dependent. DISCUSSION: CMT4J is a rapidly progressive pure motor neuron type of CMT which mimics amyotrophic lateral sclerosis. This case highlights the course of the disease as it relates to the timing of symptom onset, diagnosis, and the most crippling complication that is respiratory failure. CONCLUSIONS: Peripheral neuropathies, especially in the benign phases, should provoke early and broad screening, genetic testing, and advanced planning with regard to the devastating sequelae of ascending neuromuscular weakness. DISCLOSURE: Nothing to declare. KEYWORD: Charcot Marie Tooth

Novel Variants in the FIG4 Gene Associated With Chinese Sporadic Amyotrophic Lateral Sclerosis With Slow Progression.

Background and PurposeMutations in the FIG4 gene have been linked to amyotrophic lateral sclerosis (ALS) type 11 in Caucasian populations. The purpose of this study was to identify FIG4 variants in a cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin.MethodsAll 23 exons of FIG4 were sequenced using targeted next-generation sequencing. An extensive literature review was performed to detect genotype-phenotype associations of FIG4 mutations.ResultsNo FIG4 variants were identified in the FALS patients. One novel heterozygous missense variant (c.352G>T [p.D118Y]) and one novel heterozygous nonsense variant (c.2158G>T [p.E720X]) in FIG4 were identified in two SALS patients. The p.E720X variant is interpreted as likely pathogenic while the p.D118Y variant is a variant of uncertain significance. The patient carrying the p.E720X mutation developed lower-limb-onset slowly progressive ALS, and survived for 11.5 years. The patient harboring the FIG4 p.D118Y variant also presented with progressive ALS, with the score on the ALS Functional Rating Scale–Revised (ALSFRS-R) decreasing by 0.4 per month. The rate of decrease in the ALSFRS-R scores from symptom onset to diagnosis seemed to be lower in the patients carrying FIG4 variants than the no-FIG4-mutation ALS patients in this study.ConclusionsOur findings suggest that ALS patients carrying FIG4 mutations are not common in the Chinese population and are more likely to exhibit slow progression.

Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J.

The genetic peripheral neuropathy known as Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive mutations in the FIG4 gene. The transformational success of adeno-associated virus (AAV) gene therapy for spinal muscular atrophy has generated substantial interest in using this approach to create similar treatments for CMT. In this issue of the JCI, Presa et al. provide a preclinical demonstration of efficacy using AAV-directed gene therapy for CMT4J. The study showed a dramatic improvement in both survival and neuropathy symptoms in a severe mouse model of CMT4J after administration of AAV gene therapy at several time points. The authors' approach advances the technique for delivering treatments to individuals with CMT, for which FDA-approved therapies have not yet come to the clinic.

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

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.

FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome

BackgroundCharcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. ObjectivesTo analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. MethodsPhenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts. ResultsNext generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients. ConclusionThis study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.

Whole exome sequencing establishes diagnosis of Charcot–Marie–Tooth 4J, 1C, and X1 subtypes

BackgroundCharcot–Marie–Tooth (CMT) hereditary polyneuropathies pose a diagnostic challenge. Our aim here is to describe CMT patients diagnosed by whole exome sequencing (WES) following years of fruitless testing.Methods/ResultsThree patients with polyneuropathy suspected to be genetic in origin, but not harboring PMP22 gene deletion/duplication, were offered WES. The first patient, a 66‐year‐old man, had been suffering from progressive weakness and atrophies in the lower and upper extremities for 20 years. Due to ambiguous electrophysiological findings, immune therapies were administered to no avail. Twelve years after PMP22 deletion/duplication testing, WES revealed two pathogenic variants in the FIG4 gene (p.Ile41Thr and p.Phe598fs, respectively), as a cause of CMT 4J. The second patient, a 19‐year‐old man, had been suffering from hearing and gait impairment since at least his infancy, and recently presented with weakness and dystonia of the lower extremities. In this patient, WES identified the p.Leu122Val LITAF gene variant in heterozygous state, suggesting the diagnosis of CMT 1C, several years after initial genetic analyses. The third patient, a 44‐year‐old man, presented with progressive weakness and atrophies of the lower and upper extremities since the age of 17 years old. In this patient, WES identified the hemizygous p.Arg164Gln pathogenic variant in the GJB1 gene, establishing the diagnosis of CMT X1, 8 years after testing for PMP22 deletion/duplication.ConclusionNovel diagnostic techniques, such as WES, offer the possibility to decipher the cause of CMT subtypes, ending the diagnostic Odyssey of the patients and sparing them from unnecessary and potentially harmful treatments.

Charcot Marie Tooth disease type 4J with complex central nervous system features.

We describe a family with Charcot Marie Tooth disease type 4J presenting with features of Charcot Marie Tooth disease plus parkinsonism and aphemia. Genetic testing found two variants in the FIG4 gene: c.122T>C (p.I41T) – the most common Charcot Marie Tooth disease type 4J variant – and c.1949‐10T>G (intronic). Proband fibroblasts showed absent FIG4 protein on western blot, and skipping of exon 18 by RT‐PCR. As most patients with Charcot Marie Tooth disease type 4J do not have central nervous system deficits, we postulate the intronic variant and I41T mutation together are causing loss of FIG4 protein and subsequently the central nervous system findings in our family.

Rapidly progressive asymmetrical weakness in Charcot–Marie–Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy

Charcot-Marie-Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4 sequencing identified a compound heterozygous I41T/K278YfsX5 genotype. CMT4J secondary to FIG4 mutations should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy, especially if there is a background history of a more slowly progressive neuropathy.

Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Loss of function of the FIG4 gene causes Charcot-Marie-Tooth disease (CMT)-4J with many features also found in motor neuron disease (MND). Mechanisms for the degeneration are unknown. We investigated this using Fig4-deficient pale tremor (plt) mice, a mouse model of CMT4J. Ultrastructural studies in sensory neurons of dorsal root ganglion (DRG) confirmed abundant vacuoles with membrane disruption. The vacuoles became detectable as early as postnatal day 4 in the DRG. However, the vacuoles were absent or minimal in the spinal motor neurons or cortical neurons in 2- to 5-week-old plt mice. Instead, a large number of electron-dense organelles, reminiscent of those in lysosomal storage disorders, accumulated in the motor neurons, but not in the sensory neurons of DRG. This accumulation was associated with increased levels of lysosomal proteins, such as LAMP2 and NPC1, but not mannose-6-phosphate receptor, an endosomal protein that is usually excluded from the lysosomes. Our results suggest that Fig4 deficiency affects motor neurons differently from sensory neurons by mechanisms involving excessive retention of molecules in lysosomes or disruption of vacuolated organelles. These two distinct pathological changes may contribute to neuronal degeneration.

Deleterious Variants of FIG4, a Phosphoinositide Phosphatase, in Patients with ALS

Mutations of the lipid phosphatase FIG4 that regulates PI(3,5)P(2) are responsible for the recessive peripheral-nerve disorder CMT4J. We now describe nonsynonymous variants of FIG4 in 2% (9/473) of patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Heterozygosity for a deleterious allele of FIG4 appears to be a risk factor for ALS and PLS, extending the list of known ALS genes and increasing the clinical spectrum of FIG4-related diseases.

Solitary fibrous tumor of the nasal cavity and paranasal sinuses

The solitary fibrous tumor (SFT), also known as benign fibrous mesothelioma or submesothelial fibroma is one of the different types of existing mesothelial tumors. It was originally described in the pleura by Klemper and Rabin in 1931 1 an dwa slate rreferre dt oa sa SF To fth epleur aand peritoneum with no actual mesothelial differentiation. Although the majority of these tumors are originated in the pleura, a number of extrapleural sites with no relationship to mucosal surfaces have been reported; these include the liver, parapharyngeal space, sublingual gland, tongue, vulva ,paroti dgland ,thyroid ,an dlarynx. 2 Th eSF To fthe nasal cavity and paranasal sinuses is extremely rare, with only 22 cases reported in the world literature so far. A 32-year-old man, originally from Mexico City with a family history of type 2 diabetes mellitus and hypertension presented to us with a 2-month history of bilateral nose obstruction, predominantly on the right side, greenish rhinorrhea, general malaise, and fever, all of which partially resolved after numerous medications previously given to him. Physical examination and endoscopy revealed a smooth-textured, grayish mass that completely obstructed the right nasal cavity and pushed the nasal septum toward the left side. Computed tomography showed a large mass that occupyied the entire right nasal cavity and part of the left cavity with remodeling and erosion of the nasal septum and right lateral nasal wall. The mass completely occupied the right ethmoidal sinus and part of the right sphenoidal an dmaxillar ysinuse s(Fi g1) .Administratio no fintravenous contrast revealed heterogeneous hyperdensity of the lesion. Examination of a biopsy specimen reported a benign tumor compatible with Schwannoma and functional endoscopic sinus surgery was performed. During surgery, the nasal mass was found to be originating from the right lateral nasal wall, with great vascularity and intense bleeding when manipulated with microdebrider. Approximately 60% of the mass was resected and was later sent for histopathologic analysis. A benign tumor was observed microscopically, with the presence of spindle-shaped cells with long nuclei and a moderate amount of eosinofilic cytoplasm; some areas showed interstitial dense collagen deposits while some other sabundan thyalinizatio n(Fig s2 an d3) .Fe wscattered dilated blood vessels and horseshoe-shaped vessels were seen, but there was no evidence of atypical cellularity, necrosis, hemorrhage, or an increase in the number of mitosis. Immunohistochemical staining was positive for vimentin ,CD3 4(Fi g4) ,an dCD9 9an dnegativ efo rS-10 0protein, actin and desmin, thus helping us establish a diagnosis for SFT.