Clinical Summary

• Chronic (non-episodic) quadriparesis
• Bilateral foot drop + intrinsic foot muscle weakness since age 2
• Intrinsic hand muscle weakness since age 13
• Graded (length-dependent) sensory loss in limbs
• Truncal sensory loss
• Lost proprioception
• Preserved autonomic function
• No cranial nerve involvement
• No cerebellar signs
• No cognitive/personality changes
• No family history

Differential Diagnoses

1. Charcot-Marie-Tooth Disease (CMT) - Sporadic / De Novo - Top Diagnosis

• CMT4 (Autosomal Recessive): Onset in early childhood, progressive weakness leading to inability to walk in adolescence. Both demyelinating and axonal types exist. AR inheritance means parents can be unaffected carriers, explaining the absence of family history. Key subtypes include CMT4A (GDAP1), CMT4B1 (MTMR2), CMT4C (SH3TC2). - Bradley and Daroff's Neurology, Ch. 106
• Dejerine-Sottas Disease (CMT3/DSD): Childhood onset, proximal + distal weakness, global areflexia, enlarged peripheral nerves, markedly slow conduction velocities (<10-15 m/sec). Most cases are sporadic (de novo dominant or de novo mutation). Severe sensory loss including proprioception. - Bradley and Daroff's Neurology, p. 2649
• CMT2 (Axonal, sporadic): Normal/near-normal conduction velocities, axonal loss, more sensory involvement than CMT1.

2. Hereditary Sensory and Autonomic Neuropathy (HSAN) with motor involvement

• HSAN Type II (AR, WNK1/HSN2 mutation): Pan-sensory loss beginning in infancy/childhood, involves all modalities. AR inheritance = no family history. Motor involvement can develop.
• Truncal sensory loss and proprioceptive loss fits a pan-sensory neuropathy pattern.
• Distinguishing feature: HSAN has less prominent motor involvement; here motor is prominent from age 2, making pure HSAN less likely. - Bradley and Daroff's Neurology, eTable 106.8

3. Friedreich's Ataxia (FRDA)

• Typical onset age 5-15 years
• Proprioceptive loss + sensory neuropathy + distal weakness + foot deformities (pes cavus, hammer toes) are the hallmark
• Cerebellar signs may be subtle or absent early
• Important differentiator: Cardiomyopathy (present in >90%), absent ankle jerks but extensor plantars (mixed UMN + LMN)
• The truncal sensory loss could suggest dorsal column involvement
• No autonomic dysfunction, no cranial nerve, no cognitive changes - all consistent

4. Congenital Muscular Dystrophy with Peripheral Neuropathy (e.g., MDC1A/LAMA2 deficiency)

• Merosin-deficient CMD (LAMA2): AR, onset in infancy, hypotonia, proximal > distal weakness, white matter changes on MRI, peripheral demyelinating neuropathy
• However, usually severe early-onset with profound hypotonia from birth, and often white matter abnormalities

5. Spinal Muscular Atrophy with Respiratory Distress / Distal SMA (DSMA/HMSN-V)

• Distal SMA type V: Distal weakness and foot drop
• Key difference: Pure motor without sensory involvement; this patient has prominent sensory loss - makes pure SMA less likely
• Scapuloperoneal form with distal sensory loss: A desmin gene mutation variant with areflexia and distal sensory loss has been described - Adams and Victor's, Ch. 50

6. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

• Chronic symmetric sensorimotor polyneuropathy, can present in childhood
• Proximal and distal weakness, sensory loss including proprioception
• However, CIDP is typically not present from age 2 years, tends to be more subacute, and usually responds to immunotherapy
• A pediatric relapsing-remitting course is possible
• Less likely given 15-year history with no mention of relapses/remissions or inflammatory markers

7. Spinocerebellar Ataxia / Sensory Neuronopathy

• If this were a ganglionopathy/dorsal root ganglion disease, truncal + limb sensory loss + proprioceptive loss would fit
• But the motor predominance from age 2 argues against a pure sensory neuronopathy

8. Adrenomyeloneuropathy (AMN)

• X-linked adrenoleukodystrophy in females (carrier state): Can cause progressive spastic paraparesis + peripheral neuropathy + sensory loss
• However, no cognitive/memory changes and no cranial nerve involvement somewhat fits
• Very long-chain fatty acids (VLCFA) would be elevated
• Less common in females, and onset at age 2 would be unusually early

Summary Table

Recommended Work-up to Narrow Differentials

1. Nerve conduction studies + EMG: Demyelinating (slow NCV <35 m/sec = CMT1/DSD) vs. axonal (normal NCV, low amplitude = CMT2/Friedreich's) pattern
2. MRI spine: Rule out structural/cord pathology causing truncal sensory level
3. Genetic panel: CMT multigene panel (PMP22 duplication, MPZ, GJB1/Cx32, MFN2), Friedreich's ataxia (FXN GAA repeat)
4. Echocardiogram: Cardiomyopathy would strongly support Friedreich's ataxia
5. VLCFA: If AMN is suspected
6. CSF analysis: Elevated protein in CMT1/DSD/CIDP
7. Nerve biopsy: Onion bulb formation = CMT1/DSD; axonal loss = CMT2/Friedreich's

Sources: Bradley and Daroff's Neurology in Clinical Practice, Ch. 106 (CMT/HMSN, HSAN); Adams and Victor's Principles of Neurology, 12th ed.

Distal Spinal Muscular Atrophy (dSMA) - Salient Features

Pathology

• Anterior horn cell (lower motor neuron) degeneration - pure motor neuronopathy
• No primary axonal or myelin pathology in peripheral sensory nerves
• No dorsal root ganglion involvement
• EMG: chronic neurogenic changes (large polyphasic MUPs, reduced recruitment, fibrillations/PSWs in acute phase)
• Nerve biopsy (if done): shows loss of large myelinated motor axons with sparing of sensory fibers

The Cardinal Feature: No Sensory Involvement

"A CMT phenotype without sensory involvement on either clinical or electrophysiological examination has been classified as hereditary motor neuropathy or hereditary distal spinal muscular atrophy."

• Bradley and Daroff's Neurology, Ch. 106
• SNAPs (sensory nerve action potentials) are normal
• No sensory symptoms: no numbness, no tingling, no sensory loss
• No proprioceptive deficit
• No pain or temperature loss

Motor Features (Distal-Predominant)

Classification: Types of dSMA/dHMN

Electrodiagnostic Features

Genetics

• Inheritance: AD most common; AR forms exist; X-linked rare
• Key genes: HSPB1 (17p11.2), HSPB8 (12q24), BSCL2 (11q13), GARS (7p14.3), IGHMBP2 (11q13), TRPV4 (12q24.1)
• Most are not SMN1-related (proximal SMA is SMN1/chromosome 5q; distal SMA is genetically distinct)
• No family history possible with de novo mutations or AR inheritance

How to Distinguish dSMA from CMT

Key Clinical Point for the Case

Sources: Bradley and Daroff's Neurology in Clinical Practice, Ch. 97 & 106; Harrison's Principles of Internal Medicine 22e, Table 43-4

Updated Clinical Picture

• Chronic quadriparesis with bilateral foot drop from age 2
• Intrinsic hand weakness from age 13
• Graded sensory loss in limbs + truncal sensory loss + lost proprioception
• No autonomic, cranial nerve, or cerebellar involvement
• No family history
• NEW: Scoliosis
• NCS: Severe sensory-motor AXONAL polyneuropathy - absent CMAPs, absent SNAPs, non-excitable nerves

What the NCS Tells You

Revised Differential Diagnoses (Ranked by Fit)

🔴 1. Friedreich's Ataxia (FRDA) - Now the Top Diagnosis

• Curve patterns are similar to idiopathic scoliosis
• Onset before puberty is the major factor in progression
• Kyphosis is more frequent than in idiopathic scoliosis
• Curves >60 degrees require surgical posterior arthrodesis

Source: Campbell's Operative Orthopaedics 15th Ed, Box 37.2 - "Friedreich Ataxia: Scoliosis 74%, foot deformities 59%, cardiomyopathy 40%"

🟠 2. CMT4C (AR-CMT with Scoliosis) - High Priority

• Caused by SH3TC2 gene mutation (chromosome 5q31-33)
• Autosomal recessive - explains absent family history
• Onset in early childhood with progressive weakness
• NCS typically shows demyelinating pattern (slow NCV) in most CMT4 subtypes, but severe/end-stage cases may have superimposed axonal loss making nerves non-excitable
• Scoliosis is a reported prominent feature of CMT4C specifically

Source: Bradley and Daroff's Neurology Ch. 106 - "CMT4C, characterized by frequent and severe scoliosis, is linked to chromosome 5q31-q33 and is caused by SH3TC2 gene mutation"

🟠 3. AR-CMT2 (Axonal CMT, Autosomal Recessive) with Scoliosis

• GDAP1 mutations (CMT4A) can produce axonal or demyelinating phenotypes - the axonal GDAP1 variant would produce absent responses
• Onset in early childhood, severe phenotype
• Scoliosis can develop as a secondary feature of long-standing neuromuscular weakness
• No family history consistent with AR

🟡 4. Giant Axonal Neuropathy (GAN)

• AR disorder caused by GAN gene mutation (gigaxonin protein)
• Onset in early childhood (2-3 years)
• Severe sensorimotor axonal neuropathy with absent NCS responses
• Associated features: kinky/curly hair, CNS involvement, scoliosis
• Progresses to involve brain and brainstem in late stages
• Ask about hair texture - tightly kinked hair in a non-African child is a classic clue

🟡 5. Refsum's Disease

• AR (PHYH gene) - phytanic acid accumulation
• Sensorimotor neuropathy + cerebellar ataxia + retinitis pigmentosa + ichthyosis
• Scoliosis can occur
• Check: ophthalmology (retinitis pigmentosa), skin, serum phytanic acid

🟡 6. Abetalipoproteinemia (Bassen-Kornzweig)

• AR lipid metabolism disorder
• Severe axonal sensorimotor neuropathy (absent SNAPs/CMAPs)
• Ataxia, retinitis pigmentosa, acanthocytosis on blood smear, fat malabsorption
• Low serum cholesterol, absent LDL/VLDL

Key Next Steps to Distinguish

Summary

The combination of scoliosis (74% prevalence) + severe axonal sensorimotor neuropathy (absent CMAPs/SNAPs) + childhood onset + AR inheritance (no family history) + proprioceptive loss makes Friedreich's Ataxia the leading diagnosis. CMT4C (known for prominent scoliosis), AR axonal CMT, and Giant Axonal Neuropathy are close alternatives. FXN gene testing and echocardiography should be the first investigations.