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

Abstract

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.

Figure 1

Genetic analysis in JALS patients and their clinical features. (A) Pedigree of Family 1 and haplotype analysis. Square indicates male; circle indicates female; solid symbol indicates affected individual, and arrow indicates the proband. (B) Sequence chromatograms of SPTLC1 mutation. The red arrow and red frame indicate the mutation site. (C) Amino acid conservation of the SPTLC1 mutation in multiple species. The red frame indicates the 20th amino acid in SPTLC1. (D) Distribution of SPTLC1 mutations (NM_006415.4) in JALS and HSAN1 patients. Mutations in HSAN1 are shown in blue; those in JALS are shown in black; and those in both HSAN1 and JALS are shown in green. The novel one is in red. (E) Three-dimensional structure of the human SPT complex: SPTLC1/SPLTC2/ssSPTa/ORMDL3. The red arrow indicates the position of the 20th amino acid in SPTLC1, which is close to ORMDL3. (F) Pedigree of Family 2. Square indicates male; circle indicates female; solid symbol indicates affected individual; and arrow indicates the proband. (G) Genetic spectrum in our JALS cohort. FUS mutations were identified in seven patients (43.8%), and mutations in SPTLC1, SETX, NEFH, DCTN1, and TARDBP were identified in one patient each. (H) X-ray film of the chest showed severe scoliosis in patient 1. (I) Photograph of the lower extremities from patient 1. The photo was taken at the age of 13 years in the last review and showed atrophy of the lower extremities and pes cavus. HSAN1: Hereditary sensory neuropathy type 1; JALS: Juvenile amyotrophic lateral sclerosis; SPT: Serine palmitoyltransferase.