Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges

Juvenile Amyotrophic Lateral Sclerosis is a genetically heterogeneous neurodegenerative disorder, which is frequently misdiagnosed due to low clinical suspicion and little knowledge about disease characteristics. More than 20 different genetic have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with gene variants, is the most prevalent globally. Despite several upper motor neuron-dominant forms being generally associated with long-standing motor symptoms and slowly progressive course, certain subtypes with lower motor neuron-dominant features and early bulbar compromise lead to rapidly progressive motor handicap. For some monogenic forms, there is a well-established genotypic-phenotypic correlation. There are no specific biochemical and neuroimaging biomarkers for the diagnosis of juvenile Amyotrophic Lateral Sclerosis. There are several inherited neurodegenerative and neurometabolic disorders which can lead to the signs of motor neuron impairment. This review emphasizes the importance of high clinical suspicion, assessment, and proper diagnostic work-up for juvenile Amyotrophic Lateral Sclerosis.

Citing Articles

Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.

Okubo S, Naruse H, Ishiura H, Sudo A, Esaki K, Mitsui J J Neurol. 2024; 272(1):36.

PMID: 39666121 PMC: 11638311. DOI: 10.1007/s00415-024-12776-5.

References

Arning L, Epplen J, Rahikkala E, Hendrich C, Ludolph A, Sperfeld A . The SETX missense variation spectrum as evaluated in patients with ALS4-like motor neuron diseases. Neurogenetics. 2012; 14(1):53-61. DOI: 10.1007/s10048-012-0347-4. View

Souza P, Pinto W, Batistella G, Bortholin T, Oliveira A . Hereditary Spastic Paraplegia: Clinical and Genetic Hallmarks. Cerebellum. 2016; 16(2):525-551. DOI: 10.1007/s12311-016-0803-z. View

Brooks B, Miller R, Swash M, Munsat T . El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001; 1(5):293-9. DOI: 10.1080/146608200300079536. View

de Carvalho M, Dengler R, Eisen A, England J, Kaji R, Kimura J . Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008; 119(3):497-503. DOI: 10.1016/j.clinph.2007.09.143. View

Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S . SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010; 133(Pt 2):591-8. PMC: 2822627. DOI: 10.1093/brain/awp325. View

Pupillo E, Messina P, Logroscino G, Beghi E . Long-term survival in amyotrophic lateral sclerosis: a population-based study. Ann Neurol. 2014; 75(2):287-97. DOI: 10.1002/ana.24096. View

Klim J, Vance C, Scotter E . Antisense oligonucleotide therapies for Amyotrophic Lateral Sclerosis: Existing and emerging targets. Int J Biochem Cell Biol. 2019; 110:149-153. DOI: 10.1016/j.biocel.2019.03.009. View

Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E . Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler. 2009; 10(5-6):310-23. PMC: 3515205. DOI: 10.3109/17482960802566824. View

Deng H, Chen W, Hong S, Boycott K, Gorrie G, Siddique N . Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011; 477(7363):211-5. PMC: 3169705. DOI: 10.1038/nature10353. View

10.

Yamashita S, Mori A, Sakaguchi H, Suga T, Ishihara D, Ueda A . Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: possible association of mental retardation with this mutation. J Neurol. 2011; 259(6):1039-44. DOI: 10.1007/s00415-011-6292-6. View

11.

Dohrn M, Beijer D, Lone M, Bayraktar E, Oflazer P, Orbach R . Recurrent mutation in confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2023; 95(3):201-205. PMC: 10922288. DOI: 10.1136/jnnp-2023-332130. View

12.

Lehky T, Grunseich C . Juvenile Amyotrophic Lateral Sclerosis: A Review. Genes (Basel). 2021; 12(12). PMC: 8701111. DOI: 10.3390/genes12121935. View

13.

Conte A, Lattante S, Zollino M, Marangi G, Luigetti M, Del Grande A . P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis. Neuromuscul Disord. 2011; 22(1):73-5. DOI: 10.1016/j.nmd.2011.08.003. View

14.

Ben Hamida M, Hentati F, Ben Hamida C . Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. Brain. 1990; 113 ( Pt 2):347-63. DOI: 10.1093/brain/113.2.347. View

15.

Benatar M, Wuu J, Andersen P, Bucelli R, Andrews J, Otto M . Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022; 19(4):1248-1258. PMC: 9587202. DOI: 10.1007/s13311-022-01237-4. View

16.

Turner M, Barnwell J, Al-Chalabi A, Eisen A . Young-onset amyotrophic lateral sclerosis: historical and other observations. Brain. 2012; 135(Pt 9):2883-91. DOI: 10.1093/brain/aws144. View

17.

Yamaura G, Higashiyama Y, Kusama K, Kunii M, Tanaka K, Koyano S . Novel VRK1 Mutations in a Patient with Childhood-onset Motor Neuron Disease. Intern Med. 2019; 58(18):2715-2719. PMC: 6794182. DOI: 10.2169/internalmedicine.2126-18. View

18.

Gawel M . Electrodiagnostics: MUNE and MUNIX as methods of estimating the number of motor units - biomarkers in lower motor neurone disease. Neurol Neurochir Pol. 2019; 53(4):251-257. DOI: 10.5603/PJNNS.a2019.0026. View

19.

Codron P, Cassereau J, Vourch P . InFUSing antisense oligonucleotides for treating ALS. Trends Mol Med. 2022; 28(4):253-254. DOI: 10.1016/j.molmed.2022.02.006. View

20.

Cappella M, Pradat P, Querin G, Biferi M . Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy. J Neuromuscul Dis. 2020; 8(1):25-38. PMC: 7902976. DOI: 10.3233/JND-200531. View