CMT-SGPL1

SGPL1 | 2017

What Is CMT-SGPL1?

CMT-SGPL1 is a type of CMT caused by autosomal recessive mutations in the SGPL1 gene. This gene provides instructions for making an enzyme that regulates sphingolipid signaling molecules important to nerve cell function. Mutations in the SGPL1 gene disrupt this function, leading to impaired nerve signal transmission.

CMT-SGPL1 is autosomal recessive, meaning that both copies of the gene must have a mutation to cause this subtype.

Clinical Features

The age of symptom onset in CMT-SGPL1 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-SGPL1 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-SGPL1 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-SGPL1

Classification
Unclassified Subtypes

Neuropathy Type
Axonal

Inheritance Pattern
autosomal recessive

Genetic Context

HGNC-Approved Gene Symbol
SGPL1

Gene Full Name
sphingosine-1-phosphate lyase 1

Chromosome
10q22.1

Zygosity of Responsible Variant
Compound Heterozygous

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Hypomorphic

Confidence:
High

Prediction:
Enzymatic evidence supports biallelic loss of function in CMT-SGPL1: sphingosine-1-phosphate lyase catalyzes the only irreversible exit from sphingolipid metabolism, cleaving sphingosine-1-phosphate into hexadecenal and phosphoethanolamine. Compound heterozygous and homozygous null or hypomorphic alleles leave patient cells with measurably reduced lyase activity and accumulated sphingoid base phosphates, producing S1P lyase insufficiency syndrome with steroid-resistant nephrotic syndrome, adrenal insufficiency, and peripheral nerve involvement.

Rationale:
Measured activity in patient cells, not inference from variant type, anchors this one: lyase activity falls with the alleles carried, and heterozygous parents retain enough of it to stay well. Substrate build-up sits downstream of the enzymatic block rather than being an independent toxic property of the variant protein, so replacing lyase activity addresses both.

ClinVar Pathogenic Variants

View SGPL1 ClinVar Variants

SGPL1 OMIM Entry

SGPL1 OMIM

More Info

CMT-SGPL1 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Sphingosine 1-Phosphate Lyase Deficiency Causes Charcot-Marie-Tooth Neuropathy

Authors

Atkinson, D., Nikodinovic Glumac, J., Asselbergh, B., Ermanoska, B., Blocquel, D., Steiner, R., Estrada-Cuzcano, A., Peeters, K., Ooms, T., De Vriendt, E., Yang, X. L., Hornemann, T., Milic Rasic, V., & Jordanova, A.

Publication Date
February 7, 2017

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

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