Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies

Charcot Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are genetic causes of peripheral neuropathy with overlapping clinical features. Both conditions are caused by changes in the PMP22 gene.

CMT1A

CMT1A is the most common cause of inherited neuropathy (which is also known as Charcot-Marie-Tooth disease (CMT)), accounting for up to 50% of all CMT patients. It usually presents in the first or second decade of life with a length-dependent neuropathy. A wide variability in the severity of symptoms and age at diagnosis is recognised. It is common to identify affected individuals only after a younger relative has been diagnosed.

Clinical symptoms can include:

• difficulty walking or running, with increased trips and falls;
• pes cavus and hammer toes in almost all patients;
• weakness that is more pronounced in lower limbs than in upper limbs (patients may report problems with manual dexterity); and
• fatigue (this is particularly common).

Other features, including scoliosis and hearing loss, may be reported. Loss of ability to walk unaided is rare.

Examination shows distal, symmetrical muscle wasting and weakness with lower limb predominance, loss of reflexes and sometimes tremor. Sensory symptoms, including pain and loss of proprioception and temperature discrimination, are common.

Demyelinating neuropathy is found in all patients on nerve conduction studies, with a diffuse motor and sensory nerve conduction slowing. The combined effect of dysmyelination and axonal dysfunction and loss leads to reduced sensory nerve action potentials. An intermediate-type neuropathy has been described in some patients. Nerve biopsies are not required for diagnosis.

Differential diagnosis for CMT1A includes many of the other types of demyelinating or mixed neuropathy syndromes. For this reason, if targeted testing is negative, a thorough search for other genetic or acquired causes is recommended.

HNPP

HNPP is associated with:

• recurrent, transient episodes of sensory and motor neuropathy after minimal injury (these are often non-painful and involve a single nerve such as the ulnar or peroneal nerves);
• presentation typically in the second or third decades, though as with CMT1A there is considerable clinical variability (recovery is usually complete, although a mild neuropathy may persist);
• clinical overlap with CMT1A, with some patients reporting permanent length-dependent neuropathy symptoms; and
• pes cavus, though this is less common than in CMT1A.

On examination, the patient’s presentation may be normal between episodes. Nerve conduction studies show an increase in distal motor latency, which may be most obvious in the median nerves, focal slowing at entrapment sites (such as the elbow) and normal or reduced mean corpuscular volume (MCV) and sensory findings. Nerve biopsy is not required for diagnosis.

CMT1A and HNPP are usually caused by copy number variants in the PMP22 gene. In CMT1A, a whole gene duplication is identified in the majority of affected individuals. In comparison, in patients with HNPP, a deletion of PMP22 is diagnostic. Point variants in PMP22 are a less common cause of CMT1A (present in under 5% of cases) and have also been identified as one cause of Dejerine-Sottas disease, a severe early onset demyelinating neuropathy.

Diagnosis is usually made using multiplex ligation-dependent probe amplification (MLPA) or sequencing of PMP22. Copy number variants in PMP22 are occasionally identified as incidental findings on microarray analysis.

CMT1A and HNPP are autosomal dominant conditions. An affected individual has a one-in-two (50%) chance of passing on the PMP22 variant to each child. Although most patients will have an affected parent, de novo cases have been reported.

There is currently no cure and no disease-modifying treatments for CMT1A or HNPP.

Management of CMT1A is supportive and involves physiotherapy, occupational therapy, orthopaedic and podiatry intervention, with provision of splints or orthoses where required. Follow-up in a neuromuscular service is recommended. Medication for treatment of sensory symptoms and pain is available.

Management of HNPP focuses on prevention, for example by avoidance of prolonged pressure (such as sitting with legs crossed or leaning on elbows), careful positioning during surgery and consideration of the use of medication associated with an increased risk of neuropathy. Management of persistent neuropathy symptoms is the same as for CMT1A.

For clinicians

• GeneReviews: Charcot-Marie-Tooth hereditary neuropathy
• GeneReviews: Hereditary neuropathy with liability to pressure palsies
• NHS England: National Genomic Test Directory
• OMIM: #118220 Charcot-Marie-Tooth disease, demyelinating, type 1A
• OMIM: #162500 Neuropathy, hereditary, with liability to pressure palsies
• Treat-NMD: Charcot-Marie-Tooth

References:

• Evans MRB, Reilly MM and Rossor AM. ‘A practical approach to the genetic neuropathies’. Practical Neurology 2015: volume 15, issue 3, pages 187–198. DOI: 10.1136/practneurol-2015-001095

For patients

• Charcot-Marie-Tooth UK
• NHS Health A to Z: Charcot-Marie-Tooth disease
• NHS Health A to Z: Hereditary neuropathy with pressure palsies