What are the genetic causes and management of sensory motor neuropathy of the lower limbs in children?

Genetic Causes of Sensory Motor Neuropathy of Lower Limbs in Children

Charcot-Marie-Tooth disease (CMT) is the most common genetic cause of sensory motor neuropathy affecting the lower limbs in children, with specific genetic testing recommended based on clinical presentation, electrophysiological findings, and inheritance patterns.

Primary Genetic Causes

Demyelinating Forms (CMT1)

• CMT1A (PMP22 gene duplication) is the most prevalent form, accounting for approximately 70% of demyelinating CMT cases and 76-90% of sporadic CMT1 cases 1
• CMT1B is caused by point mutations in the myelin protein zero (MPZ) gene, accounting for about 5% of CMT cases 1
• CMT1C is associated with mutations in the SIMPLE gene 2
• CMT1D results from mutations in the early growth response 2 (EGR2) gene, occurring in approximately 2.5% of cases 1

Axonal Forms (CMT2)

• CMT2A is most commonly caused by MFN2 mutations, accounting for approximately 33% of axonal CMT cases 1
• Other axonal forms map to different chromosomes: CMT2B (3q13-q22), CMT2D (7p14), CMT2E (8p21), CMT2F (1q22-q23), and CMT2G (3q13) 2

X-Linked Forms (CMTX)

• CMTX is caused by mutations in the connexin32 (Cx32/GJB1) gene, accounting for approximately 12% of all CMT cases 1
• Can present with either predominantly demyelinating or axonal phenotypes 1

Autosomal Recessive Forms

• CMT4D (HMSN-Lom): Caused by NDRG1 gene mutations 3
• CMT4C: Associated with SH3TC2 gene mutations 3
• CMT4G (HMSN-Russe): Caused by mutations in the HK1 gene 3

Clinical Presentation and Diagnosis

Typical Presentation

• Distal muscle weakness and atrophy, particularly affecting the lower limbs 4, 5
• Depressed or absent tendon reflexes 4
• Sensory loss in a "glove and stocking" distribution 1
• Foot deformities (e.g., foot drop, pes cavus) 4
• Gait abnormalities and clumsiness 4

Diagnostic Approach

1. Clinical evaluation:

   • Assess for distal muscle weakness, atrophy, and sensory deficits 1
   • Check for foot deformities and gait abnormalities 4
   • Evaluate deep tendon reflexes 1

2. Family history assessment:

   • Determine inheritance pattern (autosomal dominant, autosomal recessive, or X-linked) 1
   • Note that approximately 30% of mutations can be de novo 1

3. Electrophysiological studies:

   • Distinguish between demyelinating (slow nerve conduction velocities) and axonal (normal or slightly reduced velocities with decreased amplitudes) forms 1
   • This classification is crucial for directing genetic testing 1

4. Genetic testing:

   • Follow a tiered approach based on clinical phenotype, inheritance pattern, and electrophysiological findings 1
   • For demyelinating forms with autosomal dominant inheritance, first test for PMP22 duplication (CMT1A) 1
   • For axonal forms, first test for MFN2 mutations (CMT2A) 1
   • For cases with unclear inheritance pattern, include testing for Cx32/GJB1 mutations (CMTX) 1

Management Considerations

Supportive Care

• Physical therapy to maintain muscle strength and prevent contractures 1
• Orthotic devices for foot drop and stability 1
• Pain management for neuropathic pain 1
• Regular monitoring for progression of symptoms 1

Special Considerations

• Children under 6 years may present with nonspecific symptoms such as poorly localized pain, refusal to bear weight, irritability, or unsteady gait 1
• Be alert for signs of muscle weakness such as the Gower maneuver (using arms to push up from floor) 1
• Monitor for development of scoliosis and other orthopedic complications 1
• Avoid neurotoxic medications that may worsen neuropathy 1

Differential Diagnosis

• Guillain-Barré syndrome (typically acute onset with monophasic course) 1
• Spinal cord tethering (may present with sensorimotor disturbances of lower limbs) 1
• Drug-induced peripheral neuropathy 1
• Metabolic disorders (e.g., diabetes, hypothyroidism) 1

Genetic Counseling

• Provide information on inheritance patterns specific to the identified genetic cause 1
• Discuss recurrence risk for family planning 6
• Consider testing of asymptomatic family members when a pathogenic mutation is identified 1
• Note that CMT1A and HNPP (hereditary neuropathy with liability to pressure palsies) are reciprocal duplication/deletion syndromes 6

Prognosis

• Generally slowly progressive but variable depending on the specific genetic cause 4
• Most patients remain ambulatory throughout life, though may require assistive devices 3
• Regular monitoring for complications is essential 1