Spastic paraplegia phenotypes associated with amyotrophic lateral sclerosis-related genes: clinical, imaging and genetic analysis

doi:10.3969/j.issn.1674-8115.2026.02.016

Abstract

Abstract:

Objective ·To analyze the clinical, imaging, and genetic characteristics of spastic paraplegia (SPG) phenotypes caused by amyotrophic lateral sclerosis (ALS)-related genes. Methods ·A total of 5 pedigrees with SPG caused by ALS-related genes, admitted to the Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, from April 2017 to September 2025, were included in the study. Detailed medical histories and imaging examinations were collected, and Sanger sequencing, family co-segregation verification, and phenotype analyses were performed. Results ·Among the 5 probands, the male-to-female ratio was 3:2. The average age at onset was (18.4±21.7) years (ranging from 1 to 51 years), and the average disease duration was (12.8±13.3) years (ranging from 3 to 33 years). Physical examination revealed increased muscle tone in the lower extremities in all patients (5/5), hyperreflexia in the lower extremities (5/5), patellar clonus in 2 patients (2/5), ankle clonus in 4 patients (4/5), positive pathological signs in the lower extremities in 4 patients (4/5), and foot deformities in 2 patients (2/5). Brain MRI examinations detected abnormalities in 2 patients, specifically cerebellar and cervical spinal cord atrophy in case 1, and a small number of abnormal signals in the splenium of the corpus callosum in case 2. Peripheral nerve electrophysiological examinations indicated that a small number of spontaneous potentials were observed in both lower extremities of 1 patient, and motor evoked potentials revealed central conduction impairment. Genetic testing identified pathogenic variants in 4 different genes, namely amyotrophic lateral sclerosis 2 (ALS2), valosin-containing protein (VCP), senataxin (SETX), and never in mitosis gene A-related kinase 1 (NEK1), in these 5 patients. Among them, 2 new variants, c.3527T>C (p.Met1176Thr) and c.1732T>C (p.Ser578Pro), were newly discovered in the ALS2 gene. Conclusion ·This article analyzes the clinical heterogeneity and genetic characteristics of SPG patients caused by ALS-related genes, providing clinical evidence for accurate diagnosis and in-depth understanding of such diseases.

Key words: spastic paraplegia, amyotrophic lateral sclerosis, ALS2, VCP, SETX, NEK1

CLC Number:

R774.8

Cheng Xianru, Cao Yuwen, Tian Wotu, Cao Li. Spastic paraplegia phenotypes associated with amyotrophic lateral sclerosis-related genes: clinical, imaging and genetic analysis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(2): 256-264.

Figures/Tables 3

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References 46

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Item		Case 1	Case 2	Case 3	Case 4	Case 5
Gender		Female	Male	Male	Female	Male
Age/year		29	6	63	4	54
Age at onset/year		9	1	30	1	51
Disease duration/year		29	5	33	3.25	3
Difficulty walking		+	+	+	+	+
Delayed motor development		+	+	-	+	-
Reduced vision		-	-	-	-	+
Difficulty swallowing		+	-	-	-	-
Epileptic seizure		+	-	-	-	-
Upper limbs	HT	-	-	-	-	-
	HR	-	-	-	-	-
	MS/grade	3	5	5	5	5
Lower limbs	HT	+	+	+	+	+
	HR	+	+	+	+	+
	MS/grade	3	5	5	4+	5
Ankle clonus		+	+	-	+	+
Patellar clonus		-	-	-	+	+
Foot deformity		+	+	-	-	-
Scissor gait		-	+	+	+	+
Babinski sign		+	-	+	+	+
Brain MRI		Cerebellar atrophy and cervical spinal cord atrophy	A little abnormal signal in the splenium of the corpus callosum	-	-	-
EMG		NA	NA	NA	-	A small amount of spontaneous potentials could be seen in both lower extremities, and the MEP of the right lower extremity revealed central conduction impairment
MMSE		NA	NA	27	NA	27
MoCA		NA	NA	22	NA	25
SPRS		NA	4	20	NA	23
Mutation type		Com Het	Het	Het	Com Het	Het
Gene mutation		ALS2 c.1804C>T (p.Arg602Cys), c.3527T>C (p.Met1176Thr)	SETX c.3631C>T (p.Arg1211Cys)	NEK1 c.3842A>G(p.Gln1281Arg)	ALS2 c.1732T>C (p.Ser578Pro)、 c.4832G>A (p.Arg1611Gln)	VCP c.476G>A(p.Arg159His)
ACMG		P(PVS1+PS4+PM1+PM2+PP3+PP4)/P(PS4+PM1+PM2+PM3+PP4)	P(PVS1+PS4+PM2+PP4)	P(PVS1+PS4+PM2+PP3+PP4)	P(PS4+PM1+PM2+PM3+PP3+PP4)/P(PVS1+PS4+PM1+PM2+PP3+PP4)	P(PVS1+PS1+PS4+PS3+PM2+PM5+PP1+PP2+PP3)

Item		Case 1	Case 2	Case 3	Case 4	Case 5
Gender		Female	Male	Male	Female	Male
Age/year		29	6	63	4	54
Age at onset/year		9	1	30	1	51
Disease duration/year		29	5	33	3.25	3
Difficulty walking		+	+	+	+	+
Delayed motor development		+	+	-	+	-
Reduced vision		-	-	-	-	+
Difficulty swallowing		+	-	-	-	-
Epileptic seizure		+	-	-	-	-
Upper limbs	HT	-	-	-	-	-
	HR	-	-	-	-	-
	MS/grade	3	5	5	5	5
Lower limbs	HT	+	+	+	+	+
	HR	+	+	+	+	+
	MS/grade	3	5	5	4+	5
Ankle clonus		+	+	-	+	+
Patellar clonus		-	-	-	+	+
Foot deformity		+	+	-	-	-
Scissor gait		-	+	+	+	+
Babinski sign		+	-	+	+	+
Brain MRI		Cerebellar atrophy and cervical spinal cord atrophy	A little abnormal signal in the splenium of the corpus callosum	-	-	-
EMG		NA	NA	NA	-	A small amount of spontaneous potentials could be seen in both lower extremities, and the MEP of the right lower extremity revealed central conduction impairment
MMSE		NA	NA	27	NA	27
MoCA		NA	NA	22	NA	25
SPRS		NA	4	20	NA	23
Mutation type		Com Het	Het	Het	Com Het	Het
Gene mutation		ALS2 c.1804C>T (p.Arg602Cys), c.3527T>C (p.Met1176Thr)	SETX c.3631C>T (p.Arg1211Cys)	NEK1 c.3842A>G(p.Gln1281Arg)	ALS2 c.1732T>C (p.Ser578Pro)、 c.4832G>A (p.Arg1611Gln)	VCP c.476G>A(p.Arg159His)
ACMG		P(PVS1+PS4+PM1+PM2+PP3+PP4)/P(PS4+PM1+PM2+PM3+PP4)	P(PVS1+PS4+PM2+PP4)	P(PVS1+PS4+PM2+PP3+PP4)	P(PS4+PM1+PM2+PM3+PP3+PP4)/P(PVS1+PS4+PM1+PM2+PP3+PP4)	P(PVS1+PS1+PS4+PS3+PM2+PM5+PP1+PP2+PP3)