Paediatric motor neuronopathies

Gene: SIGMAR1

Comment on list classification: As reviewed by Luke Stuart, there is sufficient evidence available for the association of biallelic SIGMAR1 variants with distal hereditary motor neuronopathy 2. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 7 Oct 2026, 3:14 p.m. | Last Modified: 7 Oct 2026, 3:14 p.m.

Panel Version: 3.20

Green List (high evidence)

SIGMAR1 is associated with autosomal recessive distal hereditary motor neuronopathy 2 (OMIM: 605726) (accessed 10/ 2026)

Multiple unrelated patients and families with biallelic SIGMAR1 variants have been reported, typically presenting with early-onset, slowly progressive distal muscle weakness and atrophy, minimal or absent sensory involvement, and pyramidal signs (Li et al. 2015, PMID: 26078401; Lee et al. 2016, PMID: 28503617; Horga et al. 2016, PMID: 27629094; Ververis et al. 2020, PMID: 31511340). In the latter study, a homozygous missense mutation (c.500A>T, N167I) cosegregated with the dHMN phenotype in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. Recent evidence from six affected individuals in five unrelated Japanese families further supports biallelic SIGMAR1 variants as a cause of early-onset, motor-predominant axonal neuropathy with distal weakness and atrophy with pyramidal signs (Kodama et al. 2026, PMID: 42641169). Age of onset varied from <5 to 13 years of age.

Functional evidence supports impaired or reduced SIGMAR1 function as the disease mechanism. Loss of function variants including SIGMAR1 c.151+1G>T (a recurrent splicing variant) and c.500A>T, p.(Asn167Ile) have been described, the latter showing reduced protein expression, altered subcellular distribution and increased cell death (Li et al. 2015, PMID: 26078401; Ververis et al. 2020, PMID: 31511340).
Sigmar1-/- mice exhibit locomotor impairment, muscle weakness, axonal degeneration and motor-neuron loss, providing additional mechanistic support (Bernard-Marissal et al. 2015, PMID: 25678561)

A green rating is thus recommended for paediatric motor neuronopathy.

Created: 7 Oct 2026, 1:33 p.m. | Last Modified: 7 Oct 2026, 3:10 p.m.

Panel Version: 3.17

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726)

Publications

• 26078401
• 28503617
• 27629094
• 31511340
• 42641169
• 25678561

Red List (low evidence)

Juvenile ALS reported only in 1 family and distal SMA in another Chinese

Created: 2 Mar 2017, 7:41 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Red List (low evidence)

Mutations only identified in one family

Created: 18 Jan 2017, 4:25 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Amyotrophic lateral sclerosis 16, juvenile 614373

Publications

• 21842496