Differential Diagnoses

Tier 1: Most Likely Diagnoses

1. Progressive Muscular Atrophy (PMA) / "Flail Leg" Variant of ALS

2. Multifocal Motor Neuropathy (MMN) with Conduction Block

• Asymmetric and distal (often starts in one arm/hand but can affect legs)
• Slowly progressive over years
• Associated with anti-GM1 ganglioside antibodies (~50% of cases)
• Mimics ALS/PMA but responds to IVIg

3. Hereditary Motor Neuropathy (HMN) / Distal SMA ("Spinal CMT")

• Distal wasting and weakness in hands and feet
• Foot drop and intrinsic muscle wasting
• No sensory involvement on clinical or electrophysiological examination (distinguishing it from classic CMT)
• Chronic, slowly progressive course

Tier 2: Important Diagnoses to Exclude

4. Kennedy Disease (X-Linked Spinobulbar Muscular Atrophy)

• Mean onset is 30 years, but range is 15-60 years
• It is a pure LMN disorder without UMN signs
• Mild distal sensory loss is frequently present in legs but may be clinically silent
• Clues: gynecomastia, testicular atrophy, elevated CK, perioral fasciculations
• "The diagnosis should be considered in any male patient with a pure lower motor neuron disorder, particularly when the disease course is relatively indolent." - Goldman-Cecil Medicine, p. 1963
• It has a benign course and important genetic implications for the family

5. Adult-Onset SMA Type IV (SMN-Related)

6. Hirayama Disease (Juvenile Muscular Atrophy of the Distal Upper Extremity)

Tier 3: Rarer but Specific Considerations

Key Differentiating Points in This Case

Essential Investigations

1. NCS/EMG - Most critical: conduction block on motor NCS (MMN), denervation pattern, motor amplitudes, CV helps distinguish axonal vs demyelinating; sensory nerve action potentials should be normal in pure motor conditions
2. Anti-GM1 antibodies - for MMN
3. Genetic testing - androgen receptor CAG repeat (Kennedy), SMN1 copy number, PMP22 duplication, HMN gene panel
4. Hexosaminidase A/B assay - if other features suggest it
5. CK level - elevated in Kennedy, myopathies
6. MRI cervical spine - to exclude Hirayama, compressive myelopathy
7. Family history review - autosomal dominant HMN often has traceable pedigree

Differential Diagnosis - Revised by NCS Findings

Interpreting the NCS Pattern

The Classic Causes of Mononeuritis Multiplex (Axonal)

Tier 1: Top Diagnoses for This Specific Pattern

1. Vasculitic Neuropathy (Systemic or Non-Systemic)

• Pattern: Asymmetric, multifocal, axonal - exactly what is seen here
• Sensorimotor or mixed patterns depending on nerve affected
• Can be systemic (polyarteritis nodosa, ANCA-associated vasculitis, rheumatoid arthritis, SLE, cryoglobulinemia) or nonsystemic (isolated peripheral nerve vasculitis - most common form)
• "Vasculitic neuropathy... electrodiagnostic studies demonstrate a sensorimotor axonal neuropathy, often in a mononeuritis multiplex pattern" - Goldman-Cecil Medicine
• Nonsystemic vasculitic neuropathy has a peak onset at 40-70 years, fits the age perfectly
• Often painful (burning, aching), though the painless presentation here is atypical and should prompt consideration of a non-vasculitic cause, but not exclude it
• Sural nerve biopsy showing epineural vessel inflammation is diagnostic

2. Diabetic Mononeuropathy Multiplex (Diabetic Amyotrophy / Diabetic Radiculoplexus Neuropathy)

• Typically affects nerves susceptible to compression (ulnar at elbow, peroneal at fibular head), giving a bilateral but asymmetric pattern
• The motor-predominant clinical picture with subclinical sensory NCS changes is well recognized in diabetic neuropathy
• Can occur even without classical diabetic polyneuropathy
• Diabetes is one of the commonest causes of mononeuritis multiplex worldwide

3. Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

• PMP22 gene deletion on chromosome 17p11.2 (autosomal dominant)
• "Multiple recurrent local neuropathies... focal neuropathies and plexopathies are generally not painful... focal nerve lesions are often provoked by slight or even brief compression" - Adams and Victor's, p. 1340
• "In addition to recurrent focal nerve palsies, most individuals with HNPP have an underlying chronic but slowly progressive demyelinating sensorimotor neuropathy"
• However, NCS typically shows demyelinating features at compression sites (focal slowing, prolonged distal latencies) with an underlying mild sensorimotor neuropathy - axonal findings are less typical unless chronic
• The bilaterality and pattern of ulnar + median + peroneal exactly matches HNPP
• Nerve biopsy: tomaculous (sausage-shaped) myelin thickening
• Family history may be positive (autosomal dominant, but variable penetrance)

4. Leprosy (Hansen's Disease)

• "The muscle functions most affected in leprosy are... finger abduction (ulnar nerve), thumb opposition (median nerve)... and ankle extension (common peroneal nerve)" - Harrison's Principles, p. 2457
• Causes asymmetric, predominantly motor involvement of superficial nerves
• The borderline/lepromatous forms can present without obvious skin lesions, especially in endemic regions or in migrants
• Clinically silent sensory NCS abnormalities alongside motor weakness fits the pure neural form
• Thickened peripheral nerves are palpable (ulnar at elbow, peroneal at fibular head)

Tier 2: Important Additional Diagnoses

5. Multifocal Motor Neuropathy (MMN)

• However, it remains on the list because:
  • It causes asymmetric distal motor weakness in ulnar/median/peroneal distributions
  • Anti-GM1 antibodies (~50%), responds to IVIg
  • The sensory NCS changes may represent a coincidental entrapment (median at wrist, ulnar at elbow)
• "Multifocal motor neuropathy shares many diagnostic features with [ALS], including distal asymmetrical upper extremity weakness and atrophy... Key differentiating features include the time course (slowly progressive)..." - Goldman-Cecil Medicine, p. 2525

6. Sarcoid Neuropathy

• Systemic features (bilateral hilar lymphadenopathy, uveitis, skin lesions) may be absent in pure neurological sarcoidosis
• Cranial nerve involvement, especially facial nerve, is more common but limb mononeuropathy multiplex occurs
• Listed explicitly among causes of mononeuropathy multiplex - Adams and Victor's, p. 2479

7. Cryoglobulinemic Neuropathy

• Type II and III mixed cryoglobulinemia (often hepatitis C-associated) classically causes mononeuritis multiplex via immune complex-mediated vasculitis of vasa nervorum
• Pattern: asymmetric, axonal, sensorimotor
• Screen with serum cryoglobulins, HCV antibody

8. Multifocal Acquired Demyelinating Sensory and Motor Neuropathy (MADSAM / Lewis-Sumner Syndrome)

• A variant of CIDP with asymmetric, multifocal involvement of individual nerves
• Unlike MMN, affects both motor and sensory fibers
• Fits the bilateral asymmetric pattern here with both sensory and motor NCS abnormalities
• However, the pathology should be demyelinating on NCS (conduction block, temporal dispersion, slowed velocities); this patient shows axonal changes, making MADSAM less likely unless secondary axonal degeneration has supervened

Tier 3: Less Common but Relevant

Revised Hierarchy - Most to Least Likely

1. Vasculitic neuropathy (non-systemic or systemic) - axonal mononeuritis multiplex is vasculitis until proven otherwise
2. Diabetic mononeuropathy multiplex - extremely common, exact nerve pattern fits
3. HNPP - bilateral, multifocal at compression sites, ulnar + peroneal + median classic triad
4. Leprosy - if epidemiologically relevant; nerve pattern is pathognomonic
5. Cryoglobulinemic/HCV-associated neuropathy
6. MMN (with coincidental entrapment) or MADSAM
7. Sarcoidosis
8. CMT2 (axonal hereditary; needs genetic testing)

Refined Investigation Plan

Clinical Synthesis - Pattern Recognition

1. Onset in infancy - very early, suggesting a severe hereditary form
2. Trunk sensory loss - highly unusual in simple CMT; suggests dorsal root ganglia or spinal cord involvement
3. Preserved cerebellar function despite profound sensory loss - atypical for Friedreich's ataxia but does not exclude it (cerebellar signs can be overshadowed)
4. Scoliosis - classic accompaniment of chronic neuropathy/neuronopathy from childhood
5. Female, no bulbar/ocular/cognitive involvement - helps narrow hereditary differentials

Differential Diagnoses - Ranked

Tier 1: Most Likely

1. Dejerine-Sottas Disease (CMT3 / Congenital Hypomyelinating Neuropathy)

• Autosomal recessive (or de novo dominant) severe demyelinating neuropathy
• Onset in infancy with hypotonia, delayed motor milestones, areflexia - characteristic
• Progressive distal > proximal weakness: foot drop, intrinsic wasting, later hand involvement
• All sensory modalities affected including trunk sensation (due to nerve root involvement)
• Scoliosis is a well-recognized complication from spinal muscle imbalance and neuropathic changes
• No cerebellar, cognitive, or cranial nerve involvement (extrinisic muscles spared)
• Motor NCV typically < 10 m/sec (extremely slow) - pathognomonic
• Caused by mutations in PMP22, MPZ (P0), EGR2, PRX genes
• "A more severe phenotype of severe demyelinating polyneuropathy with onset occurring in early childhood and very slow conduction velocities (<10 m/sec in forearm) is referred to as Dejerine-Sottas disease" - Bradley and Daroff's Neurology
• "Walking is delayed in onset and then progressively impaired... All modalities of sensation are impaired in a distal distribution, and the tendon reflexes are absent... The trunk and other cranial nerves are spared" - Adams and Victor's Principles of Neurology

2. CMT4 (Autosomal Recessive Demyelinating CMT) - Particularly CMT4C (SH3TC2) or CMT4A (GDAP1)

• Autosomal recessive - explains female presentation without obvious family history
• Early childhood onset, typically more severe than CMT1
• Scoliosis is a highlighted distinguishing feature of CMT4 vs. other CMT subtypes
• CMT4C (SH3TC2 mutation) - notable for scoliosis and cranial nerve involvement (but CN sparing still possible)
• CMT4A (GDAP1 mutation) - can be rapidly progressive with early severe motor loss
• CMT4D (NDRG1 mutation) - associated with deafness in Romani population
• Sensorimotor axonal and demyelinating components; sensory loss including trunk is possible with severe forms
• "CMT4 is a rare autosomal recessive form of CMT, typically more severe and early onset... Scoliosis and hip deformity are notable" - PM&R KnowledgeNow

3. Friedreich's Ataxia (FRDA) - Atypical / Cerebellar-Silent Form

• Classic FRDA triad: progressive ataxia, areflexia, sensory neuropathy - but cerebellar signs can be minimal or absent early, especially in this young patient
• "FA should be suspected in children or adolescents without a dominant family history presenting with slowly progressive ataxia, deep tendon reflex loss, and sensory axonal neuropathy, particularly when substantial cerebellar atrophy is not observed"
• Scoliosis is present in ~85% of FRDA patients
• Loss of JPS and vibration (dorsal column/large fiber) is the hallmark sensory pattern - exactly as seen here
• Trunk sensory loss occurs in FRDA due to degeneration of dorsal root ganglia and Clarke's column
• Normal cognition - FRDA does not affect intelligence
• NCS shows pure sensory axonal pattern (absent/reduced sensory amplitudes, normal motor velocity) - very specific
• Cardiomyopathy (hypertrophic) is associated - must be screened for
• Caused by GAA trinucleotide repeat expansion in FXN (frataxin) gene on chromosome 9q13
• Female = consistent (autosomal recessive, affects both sexes equally)
• Key distinguishing test: Frataxin gene GAA repeat expansion - diagnostic in >95%

Tier 2: Important Diagnoses to Consider

4. Abetalipoproteinemia (Bassen-Kornzweig Syndrome)

• Autosomal recessive MTTP gene mutation - impairs apoB-containing lipoprotein synthesis
• Results in severe vitamin E and other fat-soluble vitamin deficiency
• Clinical features in adolescence: progressive ataxia, sensory neuropathy (areflexia, loss of JPS/vibration), weakness, scoliosis, retinitis pigmentosa
• Early features from infancy: failure to thrive, fat malabsorption, steatorrhea, acanthocytosis
• Overlaps significantly with FRDA phenotype
• Distinguishing features: acanthocytes on blood film, very low/absent LDL and triglycerides, absent apoB, retinitis pigmentosa (not mentioned in this patient - key absence)
• Vitamin E supplementation is a treatable cause - cannot afford to miss
• Trunk sensory loss possible with severe spinocerebellar tract involvement

5. Vitamin E Deficiency Neuropathy / AVED (Ataxia with Vitamin E Deficiency)

• TTPA gene mutation causing isolated vitamin E deficiency despite normal fat absorption
• Phenotypically identical to Friedreich's ataxia - sensory neuropathy, areflexia, proprioceptive loss, scoliosis
• NCS shows sensory axonal neuropathy (absent sensory action potentials)
• Can present in childhood/adolescence
• Crucial because it is completely treatable with high-dose vitamin E supplementation
• Distinguishing from FRDA: normal frataxin gene, low serum vitamin E, no cardiac involvement

6. Refsum Disease (Heredopathia Atactica Polyneuritiformis)

• Autosomal recessive PHYH gene mutation; defective alpha-oxidation of phytanic acid
• Classic pentad: polyneuropathy + cerebellar ataxia + retinitis pigmentosa + anosmia + deafness
• However, the cerebellar component can be subtle or absent early; trunk and limb sensory loss with areflexia is prominent
• Elevated plasma phytanic acid levels - diagnostic
• Important because dietary restriction of phytol/phytanic acid reverses the neuropathy - treatable
• Scoliosis and ichthyosis can occur
• Age of onset variable - childhood to adult

7. Giant Axonal Neuropathy (GAN)

• Autosomal recessive GAN gene mutation (gigaxonin protein)
• Onset in early childhood (usually 2-3 years); progressive sensorimotor neuropathy
• Highly distinctive feature: tightly curled, frizzy hair (kinky hair) in most patients
• Severe sensorimotor neuropathy with areflexia, loss of all sensory modalities
• CNS involvement possible (seizures, optic atrophy, cerebellar signs) - but not universal early
• NCS: severe axonal or mixed neuropathy
• MRI may show white matter changes in CNS-involved cases
• If the patient has distinctly curly/kinky hair, this should strongly prompt this diagnosis

8. Severe CMT2 (Axonal, Autosomal Recessive) - Particularly CMT2A (MFN2)

• MFN2 mutations can cause severe early-onset axonal neuropathy
• Some cases have infantile or childhood onset with aggressive motor and sensory involvement
• CMT2A (dominant) but severe AR-CMT2 forms exist with childhood onset and trunk sensory loss
• Motor NCV normal or near-normal; reduced sensory and motor amplitudes

Tier 3: Broader Considerations

Differentiating Features - Comparison Table

Mandatory Investigation Algorithm

First-line (All patients)

1. NCS/EMG - Single most important test
   • NCV < 10 m/s in motor nerves → Dejerine-Sottas / CMT3 / CMT4 (demyelinating)
   • Near-normal motor NCV + absent sensory potentials only → FRDA, AVED (sensory ganglionopathy pattern)
   • Reduced motor amplitudes + reduced sensory → Axonal CMT2 / GAN
2. Serum vitamin E level - Screening for AVED and ABL (treatable!)
3. Fasting lipid profile - ABL (absent LDL/triglycerides)
4. FXN gene - GAA repeat expansion - Friedreich's ataxia
5. Blood film for acanthocytes - ABL, neuroacanthocytosis
6. Echocardiogram - FRDA-associated cardiomyopathy (hypertrophic)

Second-line

1. Comprehensive CMT genetic panel - PMP22, MPZ, EGR2, PRX (CMT3/CMT4 genes); SH3TC2, GDAP1, NDRG1 (CMT4 subtypes); MFN2 (CMT2A)
2. GAN gene sequencing - if kinky hair or very severe early axonal neuropathy
3. Plasma phytanic acid - Refsum disease
4. ARSA (arylsulfatase A) activity in leukocytes - MLD
5. Serum apoB / apolipoprotein B electrophoresis - confirm ABL if lipids are low
6. MRI brain and spine - white matter changes (MLD, Krabbe), spinal cord atrophy (FRDA), normal in CMT

Gold standard

1. Nerve biopsy (sural) - onion bulbs (CMT1/CMT3/CMT4), giant axons (GAN), sulfatide deposits (MLD), axonal loss pattern

The Highest-Priority Diagnosis Not to Miss

Case Summary - Transcribed from Image

"A 17yr ♀ patient plus chronic progressive neurological illness in the form of chronic quadriparesis, bilateral foot drop with intrinsic foot muscle weakness since starting in infancy / early childhood & intrinsic hand muscle weakness in adulthood/adolescence, with sensory loss in bilateral lower limbs with loss of JPS, with no symptoms of autonomic dysfunction & no cranial nerve deficits & no cerebellar dysfunction symptoms, with no memory disturbance & personality change - with no family history"

Synthesis of Key Diagnostic Features

The Critical Impact of "No Family History"

1. Autosomal dominant disorders (CMT1A, CMT1B, CMT2A - most common CMT forms) become less likely but NOT excluded, because:
   • Variable penetrance means an affected parent may be asymptomatic
   • De novo mutations occur in ~30-50% of CMT1B, and documented in CMT1A
   • "CMT1B: Sporadic presentation may occur in 50% of cases" - Neuromuscular Disease Center, WashU
2. Autosomal recessive disorders (CMT4, Dejerine-Sottas, FRDA, AVED, ABL, Refsum) now become the prime candidates - parents are carriers, appear unaffected, no family history expected
3. X-linked disorders (CMTX1 - GJB1 mutation) - female carriers can have mild or absent disease; affected males in family may not be known
4. Acquired causes (CIDP) remain on the list - no family history is expected

Differential Diagnoses - Fully Elaborated

Tier 1: Highest Priority (Best Clinical Fit + No Family History Expected)

1. Friedreich's Ataxia (FRDA) - Atypical Presentation

• Autosomal recessive (FXN gene, GAA trinucleotide repeat expansion, chromosome 9q13) - no family history is the rule, not the exception; parents are asymptomatic carriers
• Classic features: progressive sensory ataxia, areflexia, scoliosis, loss of JPS and vibration, distal weakness - all present in this patient
• Sensory loss in lower limbs spreading to upper and trunk - perfectly fits dorsal root ganglion degeneration pattern
• Onset typically 5-15 years - foot symptoms since infancy is earlier than typical (raises question of atypical/severe form)
• The absent cerebellar symptoms reported by patient: FRDA can present with sensory ataxia primarily (imbalance due to proprioceptive loss, not cerebellar). Cerebellar degeneration is pathologically present but clinically may be overshadowed by the sensory loss. "Friedreich ataxia: patients show an afferent/sensory ataxia as a prominent feature" - Bradley and Daroff's Neurology
• Importantly, brain/spine MRI is typically normal in FRDA - no cerebellar atrophy
• From ARCA table: "Sensory and cerebellar ataxia, square-wave jerks, areflexia, Babinski sign, scoliosis, pes cavus, cardiomyopathy, diabetes" - Bradley and Daroff's
• "FA cannot be confidently excluded on clinical grounds" without genetic testing
• Associated: hypertrophic cardiomyopathy (screened by ECG/echo), diabetes
• Diagnostic test: FXN GAA repeat expansion - confirms >95% of cases

2. Dejerine-Sottas Syndrome (CMT3 / Severe Infantile-Onset Demyelinating Neuropathy)

• Onset in infancy with hypotonia, delayed walking, severe areflexia - the earliest and most severe CMT phenotype
• Genes: PMP22, MPZ (P0), EGR2, PRX - can be autosomal dominant (de novo) or autosomal recessive; no family history expected with de novo mutations
• Progressive distal motor loss (foot drop, intrinsic wasting) + all sensory modalities including trunk
• Scoliosis develops from chronic postural/neuropathic changes
• No cerebellar, cranial nerve, or cognitive involvement
• NCS: motor NCV < 10 m/s - pathognomonic; palpably enlarged peripheral nerves may be found on examination
• "Walking is delayed in onset and then progressively impaired... All modalities of sensation are impaired in a distal distribution... The trunk and other cranial nerves are spared" - Adams and Victor's
• The progression from foot in infancy to hands in adolescence fits the gradual rostral spread of a length-dependent neuropathy

3. CMT Type 4 (Autosomal Recessive CMT) - Multiple Subtypes

• All CMT4 subtypes are autosomal recessive - parents unaffected carriers; no family history expected
• Earlier onset and more severe than CMT1/CMT2; progressive sensorimotor neuropathy
• Scoliosis is a prominent distinguishing feature of CMT4 compared to other CMT types
• Relevant subtypes:
  • CMT4C (SH3TC2) - prominent scoliosis, earlier onset, also causes mild cranial nerve involvement (absent here, but scoliosis fit is good)
  • CMT4A (GDAP1) - can be rapidly progressive, axonal or demyelinating
  • CMT4D (NDRG1) - associated with deafness (Lom disease) in Romani populations
  • CMT4B (MTMR2/SBF2) - focally folded myelin, childhood onset
• "CMT4 is a rare autosomal recessive form of CMT, typically more severe and early onset... Scoliosis and hip deformity are notable"
• NCS: markedly slowed motor NCV (demyelinating) or reduced amplitudes (axonal)
• Diagnostic test: Targeted CMT4 gene panel

4. Ataxia with Vitamin E Deficiency (AVED / TTPA Mutation)

• Autosomal recessive TTPA gene mutation → deficiency of alpha-tocopherol transfer protein → isolated vitamin E deficiency despite normal fat absorption
• Phenotype is clinically indistinguishable from Friedreich's ataxia: sensory neuropathy, areflexia, loss of JPS/vibration, scoliosis, progressive limb weakness
• From ARCA table: "Sensory ataxia, cerebellar ataxia, areflexia, Friedreich ataxia-like" - Bradley and Daroff's
• No family history expected (autosomal recessive)
• Cerebellar signs may be present but mild/absent early
• Treatable: high-dose vitamin E supplementation can halt and partially reverse progression
• Diagnostic test: Serum vitamin E level (low/undetectable) - simple, cheap, immediate

Tier 2: Important Secondary Diagnoses

5. CMT2 - Severe Autosomal Recessive Axonal Forms (AR-CMT2)

• Several AR-CMT2 subtypes exist with childhood/adolescent onset and no family history expected
• CMT2A (MFN2 mutation) - can have early severe onset; some cases have optic atrophy
• AR-CMT2A (LMNA mutation) - nuclear lamin A/C mutation; early childhood onset axonal neuropathy
• NCS: reduced motor amplitudes, normal or near-normal motor NCV (axonal pattern)
• Motor > sensory involvement in some subtypes
• "AR-CMT2 cases... childhood onset axonopathy" - multiple subtypes in the Adams & Victor CMT classification table

6. Abetalipoproteinemia (Bassen-Kornzweig Syndrome) / Hypobetalipoproteinemia

• Autosomal recessive MTTP gene mutation → absent apoB-containing lipoproteins → profound fat-soluble vitamin deficiency (vitamins A, D, E, K)
• Early infancy features: failure to thrive, steatorrhea, fat malabsorption - would likely have been noted in infancy
• Adolescent neurological features: sensory neuropathy, proprioceptive loss, areflexia, scoliosis, progressive weakness - fits this patient
• Retinitis pigmentosa (not mentioned here - its absence somewhat argues against)
• Acanthocytes on blood film
• Diagnostic test: fasting lipid profile (absent/very low LDL and triglycerides), serum apoB, blood film for acanthocytes

7. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) - Juvenile Form

• Acquired - no family history expected
• Can begin in childhood/adolescence and be slowly progressive over years
• Causes sensorimotor neuropathy with areflexia, sensory loss including proprioception, distal > proximal weakness
• "A few young patients... a gradually progressive polyneuropathy... turned out to be an acquired CIDP rather than the expected genetic type. The absence of a family history... provided hints to the acquired nature" - Adams and Victor's Principles of Neurology
• However: 17 years of progressive course from infancy strongly argues against acquired CIDP - the timing is too early and too chronic
• Would show: heterogeneous demyelination on NCS, elevated CSF protein, potential response to IVIG/steroids
• Keep on list to avoid missing a treatable cause

8. Giant Axonal Neuropathy (GAN)

• Autosomal recessive GAN gene (gigaxonin) mutation
• Onset: early childhood (typically 2-3 years); fits the infancy-onset here
• Progressive severe sensorimotor neuropathy; all modalities affected; areflexia
• Pathognomonic finding: tightly curled, frizzy kinky hair (if present, diagnosis is essentially confirmed)
• CNS involvement (cerebral white matter, cerebellar) occurs later; may be absent at age 17
• Scoliosis is a recognized association
• NCS: axonal neuropathy (markedly reduced amplitudes)
• "Kinky" hair is a mandatory examination finding to seek in this patient

Tier 3: Less Common but Clinically Important

Ranking Summary by Probability

Mandatory Investigations in Priority Order

Immediate (Same Day - Treatable Causes)

1. Serum Vitamin E level → AVED (if low = treatable)
2. Fasting lipid profile + apoB → Abetalipoproteinemia (absent LDL)
3. Peripheral blood film → Acanthocytes (ABL)
4. ECG + Echocardiogram → FRDA-associated hypertrophic cardiomyopathy

High Priority - Genetic/Metabolic

1. FXN gene GAA repeat expansion → Friedreich's Ataxia (confirms >95%)
2. NCS/EMG → Demyelinating (NCV <10 m/s = Dejerine-Sottas/CMT3; <35 m/s = CMT1/CMT4; normal NCV = axonal CMT2/FRDA)
3. CMT gene panel → PMP22, MPZ, EGR2, PRX (CMT3); GDAP1, SH3TC2, NDRG1, MTMR2 (CMT4); MFN2, LMNA (AR-CMT2)
4. Plasma phytanic acid → Refsum disease
5. Arylsulfatase A (ARSA) activity in leukocytes → MLD

Supplementary

1. MRI brain and spine → White matter changes (MLD, GAN), spinal cord atrophy (FRDA), nerve root enlargement (CMT3/CMT4)
2. CSF analysis → Elevated protein (CMT3/CMT4, CIDP); normal in FRDA
3. Hair examination → Tightly kinky/curly hair (Giant Axonal Neuropathy)
4. Nerve biopsy (sural) → Onion bulbs (demyelinating CMT/DSD), giant axons (GAN), sulfatide deposits (MLD), normal in FRDA

The Single Most Likely Diagnosis

NCS Interpretation - Clinicopathological Meaning

What "Severe Axonal Sensorimotor Polyneuropathy with Non-Elicitable Nerves" Tells Us

What This Rules OUT

What This Confirms

1. A severe hereditary axonal sensorimotor neuropathy - primarily CMT2-spectrum (axonal CMT)
2. Giant Axonal Neuropathy (GAN) - classic axonal sensorimotor NCS
3. Abetalipoproteinemia - axonal sensorimotor neuropathy
4. Severe Mitochondrial neuropathy (POLG, other mitochondrial genes)

Revised Differential Diagnoses - Post NCS

TIER 1: Most Likely (Best fit for severe axonal sensorimotor + infancy onset + no family history)

1. CMT2A - Severe Early Onset Axonal Neuropathy (MFN2 Mutation)

• MFN2 (Mitofusin-2) mutations are the most common cause of CMT2 (~20% of all axonal hereditary neuropathy)
• Most MFN2 mutations cause severe axonal neuropathy with childhood onset - specifically coined "Severe Early-Onset Axonal Neuropathy (SEOAN)"
• NCS: "Sensory and motor amplitudes are reduced or absent, and motor conduction velocities are normal or slowed to 37 m/s" - CMT Association / CMTA, 2025 - exactly matching this case
• "MFN2 mutations particularly likely to cause severe neuropathy that may be primarily motor or motor accompanied by prominent proprioception loss" - Neurology
• Can be autosomal dominant with de novo mutations (explains no family history) OR compound heterozygous/homozygous AR
• Onset: clinical onset range 3-15 years, but congenital hypotonia and early motor delay reported in severe cases
• Associated features in some: optic atrophy, CNS white matter changes on MRI (absent here, but not universal)
• Key: Wheelchair dependence common in early-onset cases - this patient has significant disability
• Diagnostic test: MFN2 gene sequencing - first-line in axonal CMT

2. Giant Axonal Neuropathy (GAN - Gigaxonin Mutation)

• Autosomal recessive GAN gene mutation (chromosome 16q24.1) - gigaxonin protein dysfunction
• "GAN presents as a slowly progressive axonal sensorimotor neuropathy in early childhood and leads to death by late adolescence" - Bradley and Daroff's Neurology
• NCS: "Reduced CMAP and SNAP amplitudes with normal to only slightly reduced conduction velocities" - Bradley and Daroff's - this is exactly "severe axonal with non-elicitable nerves"
• Clinical: distal leg weakness, peculiar gait (walking on inner foot edges), progressive
• CNS involvement develops with progression: optic atrophy, nystagmus, cerebellar ataxia, UMN signs, white matter changes on MRI - these may not yet have appeared at age 17
• Pathognomonic feature: tightly curled, frizzy kinky hair - must examine this patient's hair
• Nerve biopsy: giant axonal swellings packed with neurofilaments (beads-on-a-string)
• No family history expected (autosomal recessive)
• The fact that this patient is still alive at 17 without CNS features may suggest a milder allele or early stage
• Diagnostic test: GAN gene sequencing; sural nerve biopsy (giant axons)

3. AR-CMT2 (Autosomal Recessive Axonal CMT) - GDAP1 / LMNA / Other

• GDAP1 (CMT-RIA/CMT2K): "Axonal CMT, infantile to childhood onset, often progressing to wheelchair; vocal cord and diaphragm paralysis described" - Neuromuscular Disease Center, WashU. GDAP1 is the most prevalent gene in AR-CMT2. Causes both CMT4A (demyelinating) and CMT2K (axonal) depending on mutation type - the axonal form produces exactly this NCS pattern
• LMNA (AR-CMT2B1): Nuclear lamin A/C mutation; early childhood onset, severe axonal neuropathy, rapidly progressive
• MCM3AP: "Childhood onset, severe" - GeneReviews
• All are autosomal recessive → no family history expected
• NCS: reduced/absent motor and sensory amplitudes, normal to mildly reduced velocities

TIER 2: Important - Partially Fits but With Caveats

4. Abetalipoproteinemia (Bassen-Kornzweig Syndrome)

• NCS in ABL: axonal sensorimotor neuropathy - fits the pattern
• However, motor NCS in ABL is typically less severely affected than sensory; true "non-elicitable" motor potentials would suggest additional pathology or very advanced disease
• Clinical progression from infancy (GI) to adolescence (neuro) fits timeline
• Key clue: retinitis pigmentosa (check with ophthalmology if not done); acanthocytes on blood film
• Treatable with high-dose fat-soluble vitamins - must not miss
• Diagnostic: zero/very low LDL, absent triglycerides, absent apoB, blood film for acanthocytes

5. Friedreich's Ataxia - Re-evaluated Position

• Classic FRDA NCS shows: absent/reduced SNAPs (pure sensory axonal), with normal motor NCS
• "Sensory nerve action potentials (SNAP) are absent in >90% of patients with FA... NCV usually normal or only mildly reduced" - Medscape/Emedicine
• The presence of absent motor potentials (CMAPs) in this patient is atypical for FRDA
• However: in very severe or advanced FRDA, secondary motor axon loss can occur; some studies do report mild motor NCS changes in advanced disease
• FRDA is NOT excluded but is now a less likely primary explanation for this NCS pattern
• Still warranted: FXN GAA repeat testing (cheap, definitive)

6. Severe Mitochondrial Neuropathy (POLG1, Other Mitochondrial Genes)

• POLG1 (Alpers syndrome / POLG-ataxia): mitochondrial DNA polymerase mutation; can cause severe axonal sensorimotor neuropathy + ataxia + epilepsy + hepatic disease
• NCS: axonal sensorimotor neuropathy with severely reduced amplitudes
• The current patient has no epilepsy or hepatic features - but POLG neuropathy can present early and in isolation before other features emerge
• Maternal inheritance or autosomal recessive - no family history possible with recessive form
• Other mitochondrial neuropathy genes: TWINKLE (PEO1), TYMP (MNGIE - but causes GI dysmotility + leukoencephalopathy)
• Diagnostic: plasma lactate, mitochondrial gene panel (including POLG1), muscle biopsy with electron microscopy

7. Refsum Disease (PHYH / PEX7 Mutations)

• Classic features: peripheral neuropathy (axonal or mixed) + retinitis pigmentosa + anosmia + deafness + ichthyosis
• NCS can show severe sensorimotor axonal neuropathy in advanced disease
• Onset variable: childhood to adult
• No family history expected (autosomal recessive)
• Neuropathy can be the dominant early feature before RP becomes apparent
• Diagnostic: plasma phytanic acid level (markedly elevated)
• Treatable with dietary restriction of phytanic acid/phytol

TIER 3: Less Likely but Must Consider

Final Ranked Differential - Post NCS

Revised Investigation Priority

Immediate (Same Day - changes management)

1. Hair examination - is hair tightly kinky/curly? → GAN nearly confirmed if yes
2. Serum vitamin E level → AVED / ABL (treatable)
3. Fasting lipid profile + apoB + blood film → Abetalipoproteinemia
4. Plasma lactate (fasting) → Mitochondrial disease
5. ECG + echocardiogram → FRDA cardiomyopathy (still screen even if less likely)
6. Fundoscopy / ophthalmology referral → Retinitis pigmentosa (ABL, Refsum, GAN late)

High Priority - Genetic (Week 1)

1. MFN2 gene sequencing - first-line for axonal CMT (most common cause)
2. FXN GAA repeat expansion - FRDA (cheap, fast, must exclude)
3. GAN gene sequencing - Giant Axonal Neuropathy
4. AR-CMT2 / CMT gene panel (GDAP1, LMNA, NEFL, MED25, and next-generation sequencing of all known CMT genes)
5. Plasma phytanic acid - Refsum disease

Confirmatory

1. Sural nerve biopsy - giant axonal swellings with neurofilament accumulation (GAN) vs. loss of large myelinated axons (CMT2) vs. other specific findings
2. MRI brain + spine - white matter changes (GAN, CMT2A with CNS involvement, mitochondrial)
3. Muscle biopsy + mitochondrial respiratory chain studies - if mitochondrial suspected
4. Whole exome / genome sequencing if targeted panel negative

One Paragraph Summary