CMT-LRP12

LRP12 | 2025

What Is CMT-LRP12?

CMT-LRP12 is a type of CMT caused by autosomal dominant CGG repeat expansions in the LRP12 gene. Unlike most CMT-causing changes, this expansion is translated into an abnormal protein that forms toxic aggregates inside nerve cells, disrupting normal nerve cell function.

CMT-LRP12 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 CMT-LRP12 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.

CMT-LRP12 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

CMT-LRP12 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
CMT-LRP12

Classification
Unclassified Subtypes

Neuropathy Type
Axonal

Inheritance Pattern
autosomal dominant

Genetic Context

HGNC-Approved Gene Symbol
LRP12

Gene Full Name
Ldl Receptor Related Protein 12

HGNC Gene Alias(es)
ST7

Chromosome
8q22.3

Zygosity of Responsible Variant
Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Repeat expansion

Confidence:
Medium

Prediction:
The literature predicts a toxic gain-of-function mechanism for CMT-LRP12: a heterozygous noncoding CGG repeat expansion in the 5' region of LRP12 undergoes RAN translation into an aggregation-prone polyglycine protein that forms toxic intranuclear and cytoplasmic inclusions, rather than reducing normal LRP12 activity. This mirrors the repeat-expansion toxicity of LRP12 in oculopharyngodistal myopathy, so added wild-type is not predicted to rescue, and the toxic-species model, debated against RNA toxicity, holds confidence at medium.

Rationale:
A heterozygous noncoding CGG expansion in LRP12 is RAN-translated into a polyglycine product that forms toxic aggregates, a neomorphic gain of function, so added wild-type is not predicted to rescue. The toxic-species model remains debated against RNA toxicity, holding confidence at medium.

ClinVar Pathogenic Variants

View CMT-LRP12 ClinVar Variants

LRP12 OMIM Entry

LRP12 OMIM

More Info

CMT-LRP12 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Linking LRP12 CGG Repeat Expansion to Inherited Peripheral Neuropathy.

Authors

Hobara, T., Ando, M., Higuchi, Y., Yuan, J. H., Yoshimura, A., Kojima, F., Noguchi, Y., Takei, J., Hiramatsu, Y., Nozuma, S., Nakamura, T., Adachi, T., Toyooka, K., Yamashita, T., Sakiyama, Y., Hashiguchi, A., Matsuura, E., Okamoto, Y., & Takashima, H.

Publication Date
January 16, 2025

DOI
10.1136/jnnp-2024-333403

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

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