Clinical Characteristics of Charcot-Marie-Tooth Disease Type 4J
Abstract
Background and Objectives
Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by autosomal recessive variants in the Factor-Induced Gene 4 (FIG4) gene. Recent preclinical work has demonstrated the feasibility of adeno-associated virus serotype 9-FIG4 gene therapy. This study aimed to further characterize the CMT4J phenotype and evaluate feasibility of validated CMT-related outcome measures for future clinical trials.
Methods
This cross-sectional study enrolled children and adults with genetically confirmed CMT4J, with 2 documented disease-causing variants in the FIG4 gene. Patients were recruited through the Inherited Neuropathy Consortium network. Disease severity was assessed using standardized CMT-specific outcome measures and exploratory biomarkers including muscle MRI fat fraction, electrophysiology, and neurofilament light chain levels. Descriptive statistics and correlation analyses were conducted to explore relationships between variables.
Results
We recruited a total of 19 patients, including 14 pediatric patients (mean age 10.9 ± 3.9 years) and 5 adults (mean age 40.0 ± 13.9 years). The most frequent symptoms were gross motor delay and distal more than proximal muscle weakness, which were observed in 14 of 19 patients. The most common non-neuromuscular symptoms were cognitive and respiratory deficits, each seen in 8 of 19 patients. We denoted asymmetric weakness in 2 patients and nonuniform slowing of conduction velocities in 6 patients. Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), Pediatric Quality of Life Inventory, and Vineland Adaptive Behavior Scale scores were affected in most patients. We observed a significant positive correlation between neurofilament light chain levels and CMTPedS, but the study was underpowered to observe a correlation between CMTPedS and MRI fat fraction.
Discussion
We obtained baseline clinical and biomarker data in a broad cohort with CMT4J in pediatric and adult patients. Motor delay, muscle weakness, and respiratory and cognitive difficulties were the most common clinical manifestations of CMT4J. Many patients had nerve conduction studies with nonuniform slowing, and 2 had an asymmetric pattern of muscle weakness. We observed that the neurofilament light chain levels correlated with the CMTPedS in the pediatric population. This study showed feasibility of clinical outcomes including CMTPedS in assessment of disease severity in the pediatric patient population and provided baseline characteristics of exploratory biomarkers, neurofilament light chain levels, and muscle MRI fat fraction. The coronavirus disease 2019 pandemic affected some of the visits, resulting in a reduced number of some of the assessments.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
References
1.
Chow CY, Zhang Y, Dowling JJ, et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007;448(7149):68-72.
2.
Nicholson G, Lenk GM, Reddel SW, et al. Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4. Brain. 2011;134(pt 7):1959-1971.
3.
Beloribi-Djefaflia S, Morales RJ, Fatehi F, et al. Clinical and genetic features of patients suffering from CMT4J. J Neurol. 2024;271(3):1355-1365.
4.
Yu Y, Yin H, Ma C, et al. Case report and literature review: novel compound heterozygous FIG4 variants causing both of peripheral and central nervous system defects. Front Pediatr. 2022;10:1008251.
5.
Peddareddygari LR, Grewal RP. Clinical and genetic analysis of a patient with CMT4J. Neurol Int. 2022;14(1):207-211.
6.
Umair M, Alkharfy TM, Sajjad S, Alfadhel M. FIG4-associated Yunis-Varon syndrome: identification of a novel missense variant. Mol Syndromol. 2021;12(6):386-392.
7.
Baulac S, Lenk GM, Dufresnois B, et al. Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology. 2014;82(12):1068-1075.
8.
Lenk GM, Berry IR, Stutterd CA, et al. Cerebral hypomyelination associated with biallelic variants of FIG4. Hum Mutat. 2019;40(5):619-630.
9.
Yilihamu M, Liu X, Liu X, Chen Y, Fan D. Case report: a variant of the FIG4 gene with rapidly progressive amyotrophic lateral sclerosis. Front Neurol. 2022;13:984866.
10.
Liu CY, Lin JL, Feng SY, Che CH, Huang HP, Zou ZY. Novel variants in the FIG4 gene associated with Chinese sporadic amyotrophic lateral sclerosis with slow progression. J Clin Neurol. 2022;18(1):41-47.
11.
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. 2017;25(3):324-331.
12.
Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006;443(7112):651-657.
13.
Rudge SA, Anderson DM, Emr SD. Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. Mol Biol Cell. 2004;15(1):24-36.
14.
Botelho RJ, Efe JA, Teis D, Emr SD. Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase. Mol Biol Cell. 2008;19(10):4273-4286.
15.
Lenk GM, Ferguson CJ, Chow CY, et al. Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS Genet. 2011;7(6):e1002104.
16.
Cottenie E, Menezes MP, Rossor AM, et al. Rapidly progressive asymmetrical weakness in Charcot-Marie-Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy. Neuromuscul Disord. 2013;23(5):399-403.
17.
Hu B, McCollum M, Ravi V, et al. Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination. Ann Neurol. 2018;83(4):756-770.
18.
Shisheva A, Sbrissa D, Hu B, Li J. Severe consequences of SAC3/FIG4 phosphatase deficiency to phosphoinositides in patients with Charcot-Marie-Tooth disease type-4J. Mol Neurobiol. 2019;56(12):8656-8667.
19.
Katona I, Zhang X, Bai Y, et al. Distinct pathogenic processes between Fig4-deficient motor and sensory neurons. Eur J Neurosci. 2011;33(8):1401-1410.
20.
Jin N, Chow CY, Liu L, et al. VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse. EMBO J. 2008;27(24):3221-3234.
21.
Duex JE, Nau JJ, Kauffman EJ, Weisman LS. Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels. Eukaryot Cell. 2006;5(4):723-731.
22.
Zou J, Hu B, Arpag S, et al. Reactivation of lysosomal Ca2+ efflux rescues abnormal lysosomal storage in FIG4-deficient cells. J Neurosci. 2015;35(17):6801-6812.
23.
Ferguson CJ, Lenk GM, Meisler MH. Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet. 2009;18(24):4868-4878.
24.
Presa M, Bailey RM, Davis C, et al. AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model. J Clin Invest. 2021;131(11):e137159.
25.
Lenk GM, Meisler MH. Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice. Mol Genet Metab. 2022;137(4):382-387.
26.
Winters JJ, Ferguson CJ, Lenk GM, et al. Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4. J Neurosci. 2011;31(48):17736-17751.
27.
Shy ME, Blake J, Krajewski K, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology. 2005;64(7):1209-1214.
28.
Burns J, Ouvrier R, Estilow T, et al. Validation of the Charcot-Marie-Tooth disease pediatric scale as an outcome measure of disability. Ann Neurol. 2012;71(5):642-652.
29.
Eichinger K, Burns J, Cornett K, et al. The Charcot-Marie-Tooth Functional Outcome Measure (CMT-FOM). Neurology. 2018;91(15):e1381-e1384.
30.
Bray P, Cornett KMD, Estilow T, et al. Reliability of the Charcot-Marie-Tooth functional outcome measure. J Peripher Nerv Syst. 2020;25(3):288-291.
31.
Morrow JM, Evans MRB, Grider T, et al. Validation of MRC Centre MRI calf muscle fat fraction protocol as an outcome measure in CMT1A. Neurology. 2018;91(12):e1125-e1129.
32.
Feldman AB, Haley SM, Coryell J. Concurrent and construct validity of the Pediatric Evaluation of Disability Inventory. Phys Ther. 1990;70(10):602-610.
33.
Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P. The PedsQL Family Impact Module: preliminary reliability and validity. Health Qual Life Outcomes. 2004;2:55.
34.
Sparrow SS, Cicchetti DV. Diagnostic uses of the Vineland Adaptive Behavior Scales. J Pediatr Psychol. 1985;10(2):215-225.
35.
Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain. 2008;131(pt 8):1990-2001.
36.
Zimmermann M, Schuster S, Boesch S, et al. FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome. Parkinsonism Relat Disord. 2020;74:6-11.
37.
Wright GC, Brown R, Grayton H, et al. Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy. Clin Genet. 2020;98(2):147-154.
38.
Posada IJ, Domínguez-González C. CMT4J, parkinsonism and a new FIG4 mutation. Parkinsonism Relat Disord. 2020;81:82-83.
39.
Michaelidou K, Tsiverdis I, Erimaki S, et al. Whole exome sequencing establishes diagnosis of Charcot-Marie-Tooth 4J, 1C, and X1 subtypes. Mol Genet Genomic Med. 2020;8(4):e1141.
40.
Reilly MM, Herrmann DN, Pareyson D, et al. Trials for slowly progressive neurogenetic diseases need surrogate endpoints. Ann Neurol. 2023;93(5):906-910.
41.
Cornett KMD, Menezes MP, Bray P, et al. Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS. Ann Clin Transl Neurol. 2020;7(9):1713-1715.
42.
Burns J, Menezes M, Finkel RS, et al. Transitioning outcome measures: relationship between the CMTPedS and CMTNSv2 in children, adolescents, and young adults with Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2013;18(2):177-180.
43.
Cornett KMD, Menezes MP, Shy RR, et al. Natural history of Charcot-Marie-Tooth disease during childhood. Ann Neurol. 2017;82(3):353-359.
44.
Bas J, Ogier AC, Le Troter A, et al. Fat fraction distribution in lower limb muscles of patients with CMT1A: a quantitative MRI study. Neurology. 2020;94(14):e1480-e1487.
45.
Doherty CM, Morrow JM, Zuccarino R, et al. Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A. Ann Clin Transl Neurol. 2024;11(3):607-617.
Information & Authors
Information
Published In
Copyright
© 2024 American Academy of Neurology.
Publication History
Received: March 19, 2024
Accepted: June 24, 2024
Published online: August 12, 2024
Published in print: September 10, 2024
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
Study Funding
This study was supported by the CureCMT4J Foundation and NeuroGene.
Authors
Metrics & Citations
Metrics
Citation information is sourced from Crossref Cited-by service.
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.
If you need immediate support or to place an order, please call or email customer service:
- 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
- 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
- [email protected]
We appreciate your patience during this time and apologize for any inconvenience.
We thank Kalyvas et al. for sharing information about their interesting case in their comment on our article.1 As they indicated, they determined their patient had a missense variation of p.Arg553His, which research has not shown to cause loss of function of FIG4. Given the unusual presentation in this case, specifically the absence of demyelination and other typical features, it would be important to show a true loss of function of FIG4 before considering this variant pathogenic.
References
Author disclosures are available upon request ([email protected]).
We read with great interest the article by Sadjadi et al.1 We present our experience with a 43-year-old man with a 20-year history of progressive muscle weakness and severe asymmetric atrophy localized to the distal parts of both arms. Nerve conduction study showed a severe and asymmetric neuronopathy affecting both arms with prominent distal emphasis, whereas sensory nerve action potentials were mildly to moderately reduced throughout. No definite demyelinative features were found. Genetic testing revealed a heterozygous missense variant of the FIG4 gene identified as c.1658G>A (p.Arg553His); previous studies have not shown this variant to be related to neuropathy.
Compared with the cases described by Sadjadi et al.,1 our patient had adult-onset neuropathy in the distal parts of the upper extremities, and muscle strength was severely affected. Medical research council grade was 0/5 for extension, abduction, and adduction of the right fingers; 2/5 for flexion of the right wrist, right fingers, and extension of the left fingers; and 4/5 for extension of the right wrist. Tendon reflexes were absent. Pinprick and vibration sensation were slightly decreased distally in the lower extremities.
Overall, we think our case presents a possible novel variant for Charcot-Marie-Tooth Disease Type 4J with interesting clinical characteristics.
References
Author disclosures are available upon request ([email protected]).