HSN-1D

ATL1 | 2011

What Is HSN-1D?

HSN-1D is a type of CMT caused by autosomal dominant mutations in the ATL1 gene. This gene provides instructions for making atlastin-1, a protein that helps shape and maintain the network of membranes within nerve cells and supports the long axons of the peripheral nerves. Mutations in the ATL1 gene disrupt this function, leading to impaired nerve signal transmission.

HSN-1D is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.

Clinical Features

The age of symptom onset in HSN-1D is variable, ranging from childhood to adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.

HSN-1D symptoms may include:

  • Weakness in the feet and lower legs
  • Muscle atrophy
  • Foot drop
  • Reduced or absent reflexes
  • Reduced sensation
  • A steppage-style walking pattern
  • Foot deformities, including high arches, and hammertoes (clawed toes)
  • Progressive involvement of the hands and forearms
  • Difficulty with fine motor skills and manual dexterity
  • Additional symptoms not listed here

Disease Course

HSN-1D shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.

Clinical Basics

Subtype
HSN-1D

Classification
HSN

Neuropathy Type
Axonal

Inheritance Pattern
autosomal dominant

Genetic Context

HGNC-Approved Gene Symbol
ATL1

Gene Full Name
Atlastin Gtpase 1

Chromosome
14q22.1

Zygosity of Responsible Variant
Heterozygous

Variant Mechanism

Dominant-Negative

Details

Mechanistic basis:
Dominant-negative

Confidence:
Medium

Prediction:
The literature predicts a dominant-negative mechanism for HSN-1D: heterozygous ATL1 missense alleles produce mutant atlastin-1 subunits that incorporate into the GTPase oligomer and impair its homotypic ER membrane-fusion activity, disrupting the wild-type protein rather than acting through a simple null. Because the mutant continues to interfere with the wild-type complex, supplementation is not predicted to rescue, and no independent loss-of-function mechanism is established for this subtype.

Rationale:
Heterozygous missense atlastin-1 subunits incorporate into the oligomeric GTPase and disrupt homotypic ER fusion, so wild-type supplementation is not predicted to rescue: the signature of a dominant-negative effect. A partial haploinsufficiency contribution remains debated for ATL1, holding confidence at medium.

ClinVar Pathogenic Variants

View HSN-1D ClinVar Variants

ClinGen Curation

View ATL1 ClinGen Curation

HSN-1D OMIM Entry

HSN-1D OMIM

ATL1 OMIM Entry

ATL1 OMIM

More Info

HSN-1D Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Targeted High-Throughput Sequencing Identifies Mutations in Atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I

Authors

Guelly, C., Zhu, P. P., Leonardis, L., Papić, L., Zidar, J., Schabhüttl, M., Strohmaier, H., Weis, J., Strom, T. M., Baets, J., Willems, J., De Jonghe, P., Reilly, M. M., Fröhlich, E., Hatz, M., Trajanoski, S., Pieber, T. R., Janecke, A. R., Blackstone, C., & Auer-Grumbach, M.

Publication Date
January 7, 2011

DOI
10.1016/j.ajhg.2010.12.003

Updated: July 18, 2026 | By: K. Raymond

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