A 17-year-old patient started walking on the sides of his feet and had a tendency for footdrop since the age of 8. He was the product of a normal pregnancy and delivery. Developmental milestones were normal. He had a healthy 5-year-old brother. His mother also had clumsiness, weakness, and tingling in the legs since she was a teenager.
Past medical history was unremarkable.
General physical examination, mentation, and cranial nerves were normal. There was thinning of the legs ( Fig. 62B-1 ) with mild weakness in the hand interosseous muscles without significant atrophy and moderate bilateral weakness of the foot dorsiflexors and evertors with thinning of the anterior and posterior compartments. He had difficulty walking on his heels but could walk on his toes. Reflexes were 2+ in the upper extremities and knees but absent in the ankles. There were no pathologic reflexes. Sensory examination of proprioception, vibration, and pinprick sensation appeared grossly normal in the hands and legs except for vibration sense that was diminished in the toes and ankles. There was also decreased pinprick sensation in the toes. He had no scoliosis, high arches, hammertoes, or nerve hypertrophy. The rest of the examination was unremarkable.
What is the Differential Diagnosis?
The distal weakness, absent ankle reflexes, and mild sensory deficit indicate a predominantly axonal neuropathy. A distal muscular dystrophy or distal spinal muscle atrophy is unlikely because of this deficit. He appeared to have an axonal polyneuropathy of childhood onset; the differential diagnosis of this is very limited.
The history of neuropathy in the mother suggests an autosomal-dominant disease, although an X-linked inheritance, such as in CMTX, is also a consideration. The preserved proximal reflexes and normal vibratory sense are against CMT type 1A (CMT1A), but not CMTX or CMT2, in which proximal reflexes could be present in younger patients. Other common causes of neuropathy, such as diabetes, are unlikely. The clinical presentation suggests the axonal variant or CMT2.
An EMG Test was Performed
| Nerve and Site | Latency (ms) | Amplitude (mV) | Conduction Velocity (m/s) |
|---|---|---|---|
| Peroneal Nerve R. | Normal ≤ 5.7 | Normal ≥ 3 | Normal ≥ 40 |
| Ankle | NR | NR | – |
| Fibular head | NR | NR | NR |
| Tibial Nerve L. | Normal ≤ 5.3 | Normal ≥ 4 | Normal ≥ 40 |
|---|---|---|---|
| Ankle | NR | NR | – |
| Pop. Fossa | NR | NR | NR |
| Ulnar Nerve R. | Normal ≤ 3.6 | Normal ≥ 8 | Normal ≥ 50 |
|---|---|---|---|
| Wrist | 3.6 | 7 | – |
| Below elbow | 7.8 | 7 | 56 |
| Above elbow | 10.1 | 7 | 52 |
| Nerve and Site | Latency (ms) | Amplitude (mV) | Conduction Velocity (m/s) |
|---|---|---|---|
| Peroneal Nerve R. a | Normal ≤ 5.2 | Normal ≥ 3 | Normal ≥ 40 |
| Fibular head | 10.9 | 4 | – |
| Knee | 13.1 | 3 | 46 |
| Nerve | Latency (ms) | Normal Latency ≤ (ms) |
|---|---|---|
| Peroneal nerve R. | NR | 54 |
| Tibial nerve L. | NR | 54 |
| Ulnar nerve R. | 29.8 | 30 |
| H-reflex R. | NR | 34 |
| H-reflex L. | NR | 34 |
| Nerve | Onset Latency (ms) | Normal Onset Latency ≤ (ms) | Peak Latency (ms) | Normal Peak Latency ≤ (ms) | Amp (μV) | Normal Amp ≥ (μV) | Conduction Velocity (m/s) | Normal Conduction Velocity ≥ (m/s) |
|---|---|---|---|---|---|---|---|---|
| Sural nerve R. | NR | 3.5 | NR | 4.0 | NR | 11 | NR | 40 |
| Superficial peroneal R. | NR | 3.5 | NR | 4.0 | NR | 8–10 | NR | 40 |
| Ulnar nerve R. | 2.4 | 2.6 | 2.9 | 3.1 | 8 | 13 | 50 | 50 |
| Muscle | Insrt Activity | Fibs | Pos Waves | Fasc | Amp | Dur | Poly | Pattern |
|---|---|---|---|---|---|---|---|---|
| First dorsal interosseus L. | Norm | None | None | None | Lg | Inc | None | Full |
| Vastus lateralis L. | Norm | None | None | None | Lg | Inc | None | Full |
| Tibialis anterior L. | Inc | None | 1+ | None | Lg | Inc | None | Red |
| Gastrocnemius L. | Inc | None | 1+ | None | Lg | Inc | None | Red |
What were the EMG Findings?
Ulnar motor nerve conduction velocity and distal latency were normal; the CMAP amplitude was borderline. There was no conduction block or temporal dispersion. Tibial and peroneal nerve conduction velocities could not be measured because of lack of measurable CMAPs recorded in the foot. The peroneal conduction velocity when recorded at the tibialis anterior muscle was normal. The ulnar SNAP was of low amplitude and had normal latency. Sural and superficial peroneal SNAPs were absent as were tibial nerve H-reflexes. The ulnar F-response had normal latency. Denervation potentials with large motor unit action potentials (MUAPs) with reduced recruitment were seen in the distal legs. Large MUAPs were seen in the first dorsal interosseous. These findings indicate a chronic motor and sensory axonal neuropathy.
The patient’s mother was examined, and she had weakness distally in the limbs without high arches or hammertoes ( Fig. 62B-2 ). She had trace knee reflexes, normal reflexes in the upper extremities, and absent ankle jerks. There was absent vibration sense in the toes and decreased in the ankles, and decreased pinprick up to the mid-calf. Her EMG study also showed an axonal neuropathy.
Summary
This boy and his mother had a chronic axonal polyneuropathy; they were diagnosed as having CMT2 disease. No DNA testing was done.
Discussion
Case 62A , who had a demyelinating neuropathy and no family history, was found to have CMT1A. Her late symptom onset and prominent paresthesias were somewhat unusual.
CMT disease was named after the initial descriptions by Charcot and Marie and then by Tooth who called it peroneal muscular atrophy . The condition has a prevalence of 36–49 per 100,000 population. This neuropathy is usually subdivided into demyelinating (CMT1) or axonal (CMT2) forms, depending on the clinical and electrophysiologic findings ( Table 62B-1 lists the different types of CMT diseases as well as hereditary sensory and autonomic, and hereditary motor neuropathies).
| Disease | Inheritance Pattern | Gene or Locus | Clinical Features |
|---|---|---|---|
| HMSN | |||
| Forearm NCV usually <38 m/s | ||
| CMT1 | AD | Young adult onset, NCV 10–35 m/s | |
| CMT1A | PMP22 (usually duplication) |
| |
| CMT1B | MPZ (P 0 ) | Mutations also cause CMT2 and CMT3 | |
| CMT1C | LITAF/SIMPLE | ||
| CMT1D | EGR2 | Broad clinical spectrum (also CMT3) | |
| CMT1F | NEFL | DSS phenotype common | |
| CMT1 plus | FBLN5 | Macular degeneration; cutis laxa | |
| CMT1 | PMP2 | Classic CMT1 | |
| SNCV/CMT1 | ARHGEF10 | Asymptomatic slowed NCVs | |
| HNPP | AD | PMP22 (usually deletion) | Adult-onset episodic entrapment neuropathies, mild slowing (NCV 40–50 m/s) |
| CMT3 | Severe, early-onset demyelinating | ||
| DSS |
|
| Onset before age 3 years |
| CHN |
|
|
|
| CMT4 | AR | Childhood onset, usually severe | |
| CMT4A | GDAP1 | Both axonal and demyelinating types | |
| CMT4B1 | MTMR2 | Biopsy shows focally folded myelin | |
| SBF2/MTMR13 | Same as above ± early-onset glaucoma | |
| SBF1/MTMR5 | |||
| SH3TC2 | Scoliosis often severe, also axonal types | |
| NDRG1 | Dysmorphic features, deafness | |
| EGR2 | ||
| PRX | DSS phenotype | |
| HK1 | ||
| FGD4 | ||
| FIG4 | ||
| SURF-1 | |||
| CTDP1 | |||
| AD | ARHGEF10 | Asymptomatic NCV slowing |
| Intermediate | NCV 25–45 m/s | ||
| X | ||
| GJB1/Cx32 | Similar to CMT1, but males more severely affected, CNS involvement common | |
| AIFM1 | MR, deafness, axonal | |
| PRPS1 | Axonal CMT, deafness, optic atrophy | |
| PDK3 | Axonal CMT | |
| DRP2 | Intermediate MCVs | |
| AD | ||
| 10q24 | ||
| DNM2 | Neutropenia | |
| YARS | ||
| MPZ | ||
| IFN2 | Focal segmental glomerulosclerosis | |
| GNB4 | ||
| AR | ||
| GDAP1 | ||
| KARS | ||
| PLEKHG5 | ||
| COX6A1 | ||
| NCV >38 m/s | ||
| AD | Young adult onset | |
|
| Most common; also HMSN V (optic atrophy), VI (spasticity), and early onset | |
| RAB7 | Severe sensory loss like HSAN-1 | |
| TRPV4 | Vocal cord/diaphragm weakness | |
| GARS | Arm > leg, motor predominant, similar to dHMN caused by BSCL2 mutations | |
| NEFL | Allelic with CMT1E; variable phenotype | |
| HSP27 (HSPB1) | Motor predominant | |
| 12q12–13.3 | Proximal > distal weakness | |
| GDAP1 | Allelic with CMT4A | |
| MPZ (P 0 ) | Cough, pain, autonomic/pupil, deafness | |
| HSP22 (HSPB8) | Motor predominant, allelic with HMNIIa | |
| DNM2 | Intermediate or CMT2; cataracts; ophthalmoplegia; ptosis | |
| AARS | ||
| LRSAM1 | ||
| DHTKD1 | ||
| MARS | Late onset | |
| NAGLU | Late onset painful sensory predominant | |
| HARS | ||
| VCP | ||
| MORC2 | Pyramidal signs | |
| |||
| DCAF8 | Childhood onset | |
| TUBB3 | ||
| DGAT2 | ||
| JAG1 | Vocal fold paralysis | |
| KIF5A | ||
| TFG | Proximal > distal | |
| AR | ||
| LMNA | Also called CMT2B1 and CMT4C1 | |
| MED25 | ||
| HINT1 | ||
| TRIM2 | ||
| IGHMBP2 | ||
| HSJ1 | ||
| KIAA1840 | ||
| AR/AD | MME | Dominant mutations cause late onset |
| HSANs a and HMNs | |||
| Sensory (± autonomic) neuropathy | ||
| AD | SPTLC1 | Late onset, slowly progressive sensory axonal neuropathy ± SNHL, weakness |
| AD | 3p24-p22 | Variant with cough, GERD, deafness |
| AD | SPTLC2 | |
| AD | ATL1 | |
| AR | HSN2 | Congenital sensory loss, acral mutilation |
| AR | IKBKAP | Severe dysautonomia, Ashkenazi Jews |
| AR | TRKA | Anhidrosis, acral mutilation, ± CNS |
| AR | NGFB | Congenital insensitivity to pain |
| AR | DST | Severe autonomic dysfunction, death by age 2 |
| AD | SCN11A | Congenital insensitivity to pain, hyperhidrosis, GI dysfunction |
| AR | PRDM12 | Congenital insensitivity to pain |
| Distal wasting and weakness | ||
| AD | HSPB8(HSP22) | Adult onset, allelic with CMT2L |
| AD | HSP27(HSPB1) | Allelic with CMT2F |
| AD | GARS | Upper limb predominant |
| AD | BSCL2 | Allelic with SPG17/Silver syndrome |
| AR | IGHMBP2 | Severe infantile respiratory distress/SMARD |
| AD | 2q14 | Adult onset, vocal cord paralysis |
| AD | DCTN1 | Same as above |
| X | Xq13.1-q21 | |
| AR | 9p21.1-p12 | Childhood onset (Jerash type) |
| X | Androgen receptor (CAG rpt) | Adult onset bulbar symptoms, proximal weakness, sensory neuronopathy, and gynecomastia |
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