Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

Area of Science:

• Neurology
• Genetics
• Metabolic Disorders

Background:

• Cobalamin C (cblC) deficiency impacts nervous system function throughout life.
• Neurologic symptoms are often the initial or sole indicators of cblC defects.
• Peripheral neuropathy is a recognized yet frequently overlooked complication of cblC deficiency, particularly in late-onset forms linked to MMACHC gene mutations.

Purpose of the Study:

• To elucidate the clinical, electrophysiological, and pathological characteristics of late-onset cobalamin C (cblC) disease.
• To better understand the presentation of peripheral neuropathy in this specific patient group.

Main Methods:

• Retrospective analysis of patients diagnosed with late-onset cblC disease over a three-year period.
• Confirmation of neuropathy via nerve conduction studies.
• Histopathological examination of sural nerve biopsies in two patients.

Main Results:

• Eight patients with a mean onset age of 16.25 years were identified.
• All patients exhibited methylmalonic aciduria and homocysteinemia, with compound heterozygous MMACHC gene mutations, notably c.482G>A in 7/8.
• Clinical findings included limb weakness and cognitive impairment, with five patients diagnosed with sensorimotor axonal polyneuropathy; sural biopsies revealed fiber loss and crystalline inclusions in Schwann cells.

Conclusions:

• Late-onset cblC disease can manifest as a heterogeneous distal axonal neuropathy.
• The c.482G>A mutation in the MMACHC gene appears to be a prevalent mutation associated with late-onset cblC disease.