Juvenile Amyotrophic Lateral Sclerosis: A Review

Lehky, Tanya

doi:10.3390/genes12121935

Cited by 27 publications

(34 citation statements)

References 78 publications

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“…A rare and expanding subgroup of such cases includes juvenile ALS (JALS), with onset of motor compromise before age 25. JALS is commonly misdiagnosed and underrecognized in clinical practice, mainly due to low disease awareness and several diagnostic misconceptions [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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

Souza,

Serrano,

Farias

et al. 2024

Genes

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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 loci 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 FUS 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.

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Section: Introductionmentioning

confidence: 99%

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

Souza,

Serrano,

Farias

et al. 2024

Genes

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“…Over the last 30 years, more than ten causative genes have been identified in JALS. [3] The SPTLC1 gene encodes the long-chain base subunit one of serine palmitoyltransferase (SPT), which is the critical rate-limiting enzyme in the initial step of sphingolipid biosynthesis. [4] In 2001, SPTLC1 was identified as the causative gene for hereditary sensory neuropathy type 1 (HSAN1), [5] and mutations identified in patients with HSAN1 reduced SPT activity, leading to the accumulation of pathogenic and neurotoxic sphingolipids.…”

Section: Introductionmentioning

confidence: 99%

“…It is universally known that genetics play significant roles in the pathogenesis of JALS. Over the last 30 years, more than ten causative genes have been identified in JALS [3] …”

Section: Introductionmentioning

confidence: 99%

Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations

Wang

Wei

et al. 2023

Chinese Medical Journal

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Background:Juvenile amyotrophic lateral sclerosis (JALS) is an uncommon form of amyotrophic lateral sclerosis whose age at onset (AAO) is defined as prior to 25 years. FUS mutations are the most common cause of JALS. SPTLC1 was recently identified as a disease-causative gene for JALS, which has rarely been reported in Asian populations. Little is known regarding the difference in clinical features between JALS patients carrying FUS and SPTLC1 mutations. This study aimed to screen mutations in JALS patients and to compare the clinical features between JALS patients with FUS and SPTLC1 mutations.Methods:Sixteen JALS patients were enrolled, including three newly recruited patients between July 2015 and August 2018 from the Second Affiliated Hospital, Zhejiang University School of Medicine. Mutations were screened by whole-exome sequencing. In addition, clinical features such as AAO, onset site and disease duration were extracted and compared between JALS patients carrying FUS and SPTLC1 mutations through a literature review.Results:A novel and de novo SPTLC1 mutation (c.58G>A, p.A20T) was identified in a sporadic patient. Among 16 JALS patients, 7/16 carried FUS mutations and 5/16 carried respective SPTLC1, SETX, NEFH, DCTN1, and TARDBP mutations. Compared with FUS mutation patients, those with SPTLC1 mutations had an earlier AAO (7.9 ± 4.6 years vs. 18.1 ± 3.9 years, P < 0.01), much longer disease duration (512.0 [416.7–607.3] months vs. 33.4 [21.6–45.1] months, P < 0.01), and no onset of bulbar.Conclusion:Our findings expand the genetic and phenotypic spectrum of JALS and help to better understand the genotype–phenotype correlation of JALS.

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“…One of the main differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes detected in JALS (40%) than in adult-onset ALS (around 10%) [ 2 , 6 , 7 ]. The frequencies of associated genes are also different between the two forms of onset.…”

Section: Introductionmentioning

confidence: 99%

“…The frequencies of associated genes are also different between the two forms of onset. A recent review of JALS [ 7 ] identified FUS (fused in sarcoma), SETX (Senataxin), and ALS2 (Alsin) as the most common genes reported in the literature. In contrast, pathogenic variants in genes commonly associated with adult forms, such as SOD1 (copper–zinc superoxide dismutase) or TARDBP (transactive response DNA-binding protein), were reported less frequently, and C9orf72 (chromosome 9 open reading frame 72), the most prevalent inherited gene in adult disease, has not been reported in childhood [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature

Sánchez-Tejerina¹,

Restrepo-Vera²,

Rovira-Moreno

et al. 2022

Genes

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants

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Juvenile Amyotrophic Lateral Sclerosis: A Review

Cited by 27 publications

References 78 publications

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

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

Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations

An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature

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