Differential Diagnoses

Clinical Summary (from the case)

• 17-year-old female
• Chronic, slowly progressive quadriparesis
• Bilateral foot drop + intrinsic foot muscle weakness - onset age 2 years
• Intrinsic hand muscle weakness - onset age 13 years (distal upper limbs later)
• Graded (length-dependent) sensory loss in limbs + truncal sensory loss
• Lost proprioception
• No autonomic dysfunction
• No cranial nerve deficits
• No cerebellar signs
• No cognitive/memory/personality changes
• No family history

Differential Diagnoses (Ranked by Likelihood)

1. Charcot-Marie-Tooth Disease (CMT) - Most Likely

• Onset in first to third decade; bilateral foot drop is classic
• Distal weakness progresses from legs to hands ("inverted champagne bottle" legs, intrinsic hand wasting in adolescence)
• Sensory loss to all modalities, including proprioception, though often asymptomatic subjectively
• Pes cavus / hammer toes frequently present
• No autonomic dysfunction (autonomic system largely preserved)
• No cranial nerve or cerebellar involvement
• CMT1 (demyelinating, PMP22 duplication) - onset 1st decade, NCV <38 m/s
• CMT2 (axonal) - onset 2nd decade, NCV normal/mildly reduced
• CMT4 (autosomal recessive forms) - can explain absent family history in a sporadic/recessive presentation
• The absent family history in this patient fits a recessive form (CMT4) or a de novo mutation

"CMT1 is the most common form of hereditary neuropathy. Affected individuals usually present in the first to third decade with distal leg weakness (e.g., foot drop)... reduced sensation to all modalities is apparent on examination." - Harrison's Principles of Internal Medicine 22E

"In adolescence, an 'inverted champagne bottle' appearance of the forelegs may become apparent... foot-drop, ankle fractures, need for podiatric treatment at an early age." - Adams and Victor's Neurology, 12th Ed.

2. Hereditary Sensory and Motor Neuropathy - Dejerine-Sottas (CMT3 / HMSN III)

• Severe demyelinating neuropathy, often presents in infancy
• More severe than CMT1A, with marked sensory loss and proprioceptive loss
• Autosomal recessive or dominant; can present sporadically (no family history)
• "Onion bulb" formations on nerve biopsy
• Very slow nerve conduction velocities (<10-15 m/s)
• Consistent with severe childhood onset + proprioceptive loss in this patient

3. Friedreich's Ataxia (Differential - requires exclusion)

• Autosomal recessive; no family history expected
• Onset childhood/adolescence (typically age 5-15)
• Sensory neuropathy (loss of proprioception and vibration) + pyramidal signs
• However: cerebellar ataxia is cardinal in Friedreich's, and this patient has NO cerebellar signs - argues strongly against
• Cardiomyopathy and diabetes expected in later stages
• Can be excluded if cerebellar signs, dysarthria, and nystagmus are truly absent

4. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

• Acquired demyelinating neuropathy; proximal and distal weakness + sensory loss
• Typically adults, but childhood/juvenile CIDP exists
• Proprioceptive loss common
• No autonomic or cranial nerve involvement in typical forms
• Distinguished from CMT by: CSF showing elevated protein, nerve biopsy, NCV studies, and response to immunotherapy (steroids, IVIG)
• The very long (15-year) duration without progression pattern makes classical CIDP less likely; however, chronic forms can be slowly progressive

5. Hereditary Spastic Paraplegia (HSP) with Peripheral Neuropathy

• Autosomal dominant/recessive; can be sporadic
• "Complicated" HSP forms involve peripheral neuropathy + sensory loss
• Spasticity + weakness in legs is typical; upper limb involvement occurs in severe forms
• Can present in childhood
• Distinguishing features: upper motor neuron signs (spasticity, hyperreflexia) would be expected - need to examine tone/reflexes
• Absent autonomic, cranial nerve, cerebellar features fits

6. Spinal Muscular Atrophy (SMA) Type III (Kugelberg-Welander) - Less Likely

• Autosomal recessive; can present sporadically (no family history)
• Onset in childhood/adolescence (type III: age 2-17)
• Proximal > distal weakness typically; foot drop can occur
• Sensory loss is NOT a feature of classic SMA - purely motor disorder
• The presence of graded sensory loss, proprioceptive loss, and truncal sensory loss argues strongly against pure SMA
• Would need to exclude as a motor component

7. Spinal Cord Pathology - Subacute Combined Degeneration or Structural Lesion

• Truncal sensory loss in this case is an atypical feature for pure peripheral neuropathy - raises the possibility of a spinal cord component
• Subacute combined degeneration (B12 deficiency): posterior column loss (proprioception) + lateral column (motor) - but usually acquired in adults
• Syringomyelia or intramedullary spinal cord tumor: can produce dissociated sensory loss + motor weakness starting distally, can be present from childhood if congenital
• Truncal sensory loss + limb proprioceptive loss should prompt MRI spine

8. Adrenomyeloneuropathy (AMN)

• X-linked (females can be carriers with mild disease; full disease in males)
• Peripheral neuropathy + spinal cord involvement
• Onset in adolescence/young adulthood
• Sensory loss + motor weakness
• Rare in females but incomplete forms exist
• Would check plasma very long chain fatty acids (VLCFA)

Summary Table

Recommended Investigations to Narrow Diagnosis

1. Nerve conduction studies (NCS) + EMG - most important: will distinguish demyelinating (CMT1) vs. axonal (CMT2), acquired vs. inherited
2. MRI spine (cervical + thoracic) - to explain truncal sensory loss and rule out structural/cord pathology
3. Genetic panel (CMT/HMSN panel: PMP22 duplication/deletion, MPZ, GJB1, MFN2, etc.)
4. CSF analysis - if CIDP is considered (elevated protein)
5. Sural nerve biopsy - onion bulbs suggest CMT1/CMT3
6. B12, methylmalonic acid - screen for subacute combined degeneration
7. Plasma VLCFA - screen for adrenoleukodystrophy/AMN
8. Echocardiogram + blood glucose - if Friedreich's ataxia remains in differential

Sources: Harrison's Principles of Internal Medicine 22E; Adams and Victor's Principles of Neurology, 12th Ed.; Bradley and Daroff's Neurology in Clinical Practice