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Gene: SPG11

Green List (high evidence)

OMIM:
Charcot-Marie-Tooth disease type 2X (CMT2X) is an autosomal recessive, slowly progressive, axonal peripheral sensorimotor neuropathy characterized by lower limb muscle weakness and atrophy associated with distal sensory impairment and gait difficulties. Some patients also have involvement of the upper limbs. Onset usually occurs in the first 2 decades of life, although later onset can also occur (summary by Montecchiani et al., 2016). Mean age of onset 11.4 years.

Hereditary spastic paraplegia (SPG or HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. SPG11 is a form of complicated SPG, in that it has neurologic features in addition to spasticity.

Autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5) is a neurodegenerative disorder characterized by onset of upper and lower motor neuron signs before age 25. Affected individuals have progressive spasticity of limb and facial muscles associated with distal amyotrophy. The disorder is slowly progressive, with cases of prolonged survival of more than 3 decades (summary by Orlacchio et al., 2010).

These 3 conditions represent a spectrum of disease and ClinGen lumps all 3 conditions under hereditary spastic paraplegia 11 MONDO:0011445

Created: 25 Oct 2024, 5:45 a.m. | Last Modified: 31 Oct 2024, 1:30 a.m.

Panel Version: 1.525

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hereditary spastic paraplegia 11 MONDO:0011445

Green List (high evidence)

Complex SPG with central involvement, including white matter changes. Variable age of onset, including in childhood.

Bi-allelic variants in this gene also cause spastic paraplegia-11 (OMIM# 604360) but also juvenile amyotrophic lateral sclerosis-5 (OMIM# 602099), and CMT2X. Same variants have been reported in association with different phenotypes, poor genotype-phenotype correlation.

Recent review of >300 individuals with SPG11-related disease. Mean age at onset was 13.10 ± 3.65 years, with initial symptoms like gait disturbance (107/195, 54.87%) and intellectual disability (47/195, 24.10%). Cognitive decline (228/270, 84.44%) was the most common complex manifestation stepped by dysarthria (134/195, 68.72%), neuropathy (112/177, 63.28%), amyatrophy, sphincter disturbance (60/130, 46.15%) and ataxia (90/194, 46.39%).

Created: 22 Jul 2022, 2:47 a.m. | Last Modified: 22 Jul 2022, 2:47 a.m.

Panel Version: 0.61

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 11, autosomal recessive (MIM#604360)

Publications

• 33581793