Course Authors

James R. Lupski, M.D., Ph.D. and David W. Stockton, M.D.

Dr. David W. Stockton has an undergraduate degree in electrical engineering, a masters in computer science and holds two U.S. patents in computer engineering. After receiving his M.D. from the University of Michigan, David completed his post-doctoral training at Michigan. A board certified internist, he is currently an assistant professor in medical genetics at Baylor College of Medicine. Dr. Stockton reports no commercial conflict of interest. In the last three years, Dr. Lupski has received grant/research support from WIH, MDA, FFB and Merck & Co., Inc.He has also served as a consultant for Athena Diagnostics. This presentation will include discussion of commercial products and services.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Understand the impact of inherited peripheral neuropathies

• Generate an appropriate differential diagnosis

• Proceed with a diagnostic work-up to arrive at the definitive diagnosis.

 

Background

Inherited peripheral neuropathies are a common and heterogeneous group of disorders.(1) The overall prevalence has been estimated from as low as 1 in 12,000(2) to as high as 1 in 2,500.(3) This wide estimation is likely due to the variability in clinical expression and a low probability of ascertainment for some of the disorders in this group, especially those with mild phenotypic features. Nevertheless, this translates to between 20,000 and 100,000 affected people in the United States alone.

The disorders to be discussed here include Charcot-Marie-Tooth disease [MIM 118200, 118210, 118220, 159440, 214400, 302800, 304040, 600882, 601097, 601098, and 601382145900], and Hereditary Neuropathy with Liability to Pressure Palsies [MIM 162500]. In the absence of a positive family history, these diagnoses can be very difficult to make. There are no unique clinical symptoms or signs to distinguish them from other inherited or acquired peripheral neuropathies. Pes cavus and hypertrophic nerves are suggestive of an inherited form of neuropathy, as opposed to an acquired one. The increasing molecular understanding enables DNA diagnostic testing to definitively rule in or rule out these diagnoses.

Charcot-Marie-Tooth Disease (CMT)

Charcot-Marie-Tooth disease was first described in 1886 by Jean Martin Charcot and Pierre Marie,(4) and, separately, by Howard Henry Tooth(5) as a progressive muscular atrophy. The inherited or familial nature was noted from the initial description, although this was before Mendel's work was widely known. Charcot and Marie postulated the disease to be a myelopathy, while Tooth proposed it to be a neuropathy, as it turned out to be.

CMT is the most common inherited disorder of the peripheral nervous system. It is itself, however, a heterogeneous group of disorders (as implied by the list of MIM numbers above). This syndrome is subdivided into two distinct groups based on electrophysiological and pathologic studies. CMT type 1 is the demyelinating form with moderately to severely slowed motor nerve conduction velocities (NCVs), absent deep tendon reflexes (DTRs), and "onion bulb" formation on peripheral nerve biopsy. CMT type 2 is the neuronal form with normal or mildly reduced NCVs of decreased amplitude, normal DTRs and no hypertrophic features on peripheral nerve biopsy.

Clinical Features

CMT, typically, has an insidious onset of a slowly progressive weakness of the distal limb muscles. Symptoms usually appear in the first two decades of life. Muscle weakness is first noted in the distal lower extremities resulting in foot drop. Patients frequently describe tripping and spraining their ankles. The foot drop also forces a gait with highly lifted knees referred to as "steppage" or "equine". Pes cavus deformity develops with age. Atrophy of the distal leg muscles gives a "stork leg" or inverted champagne bottle appearance. Leg cramps after exercise and cold intolerance are also common complaints. A late development in the course of the disease is intrinsic hand muscle weakness and patients complain of difficulties with snaps, buttons or zippers. Severe cases may develop claw-hand deformities. DTRs disappear early in the ankle and the loss progresses proximally. Sensory symptoms are less significant but may include loss of pinprick sensation in a stocking distribution in the feet and legs, and decreased temperature sensation.

Electrophysiologic studies show uniform, bilateral and symmetric abnormalities. They are usually present by two years of age and do not significantly change after age five years. The severity of the disease correlates with the amplitude reduction of compound muscle action potentials better than to the degree of conduction slowing. As noted above, CMT type 1 and CMT type 2 can usually be differentiated by NCVs, as CMT type 1 shows slowing with relatively normal amplitude, while CMT type 2 shows decreased amplitude with relatively normal velocity.

Peripheral nerve biopsies are also able to differentiate between CMT type 1 and type 2. In CMT type 1, there are decreased numbers of myelinated fibers with hypertrophic changes due to "onion bulb" formations. The "onion bulb" structures are circumferentially directed Schwann cells around myelinated and demyelinated internodes. In CMT type 2 there are few, if any, hypertrophic changes, but axonal loss is evident.

Genetics and Molecular Biology

CMT is also genetically heterogeneous. It is inherited in an autosomal dominant, autosomal recessive and X-linked pattern. The gene has been identified for three types of CMT type 1. There are no specific genes yet identified for CMT type 2, although three genetic loci have been identified, one on chromosomes 1p35-p36, 3q and 7. There is also no gene yet identified for autosomal recessively inherited CMT although three genetic loci have been identified on chromosomes 8q, 5q and 11q.

CMT1A is inherited in an autosomal dominant pattern although approximately 10% of cases result from new mutations. The molecular mechanism for CMT1A, which is the most common cause of CMT, is the best understood. In more than 70% of inherited and 90% of sporadic CMT type 1 cases, there is a 1.5 megabase duplication of DNA on chromosome 17p11.2-12. This duplication results from an unequal recombination event during meiosis between repeated sequences of DNA flanking the region. This recombination event results in one gamete having a 1.5 megabase duplication and another having a 1.5 megabase deletion. The deletion is the most common cause of hereditary neuropathy with liability to pressure palsies, as will be discussed later. This duplicated stretch of DNA in CMT1A results in an increased dosage effect of the duplicated genes. One of the genes in this region is peripheral myelin protein 22 (PMP22) and is believed to cause the peripheral neuropathy through trisomic over expression. Point mutations in this gene are also a rare cause of CMT type 1.(6)

CMT1B is also inherited in an autosomal dominant pattern. By definition, CMT1B is caused by mutations in the gene for myelin protein zero (MPZ) which is located on chromosome 1q21.2-q23. The crystal structure of myelin protein zero has shown that its extracellular domain forms a homo-tetramer that then associates with another homo-tetramer of the cell membrane in apposition. This has been described as a "molecular Velcro" between the membranes.(7) This functions in the wrapping and compacting of the myelin sheath around the neuronal axon.(8) Mutations in MPZ have also been associated with the diagnoses of Dejerine-Sottas syndrome and Congenital hypomyelination.(9)

CMTX is clinically a type 1 CMT that is inherited in an X-linked pattern. Males with CMTX are usually much more severely affected than females. In fact, females with CMTX may appear more like CMT type 2 than CMT type 1. CMTX is caused by mutations in connexin 32 (Cx32) which is located on chromosome Xq13.1.

Hereditary Neuropathy With Liability to Pressure Palsies (HNPP)

Hereditary neuropathy with liability to pressure palsies was first described in detail in 1945 by De Jong.(10) Its familial nature was also noted in the initial description. HNPP is much less commonly diagnosed than CMT. This is likely because of its milder clinical phenotype since there is no known reason for the new mutations causing HNPP to be any less frequent than those causing CMT1A. HNPP is much less heterogeneous than CMT, with no clinical subtypes or known genetic heterogeneity. HNPP is less severe than CMT and usually requires some environmental influence or trauma to produce symptoms. This "trauma" may be as minor as the crossing of the patient's legs and results in parethesias. Complete recovery is typical. However, this may take several weeks to several months.(11)

Clinical Features

Onset of symptoms may be sudden or insidious and slow. Most patients first develop palsies between 25 and 45 years of age although this may vary significantly. Some evidence of nerve traction or pressure is usually evident from the patient's history. Carpal tunnel syndrome and other nerve entrapment syndromes are frequent manifestations. Most patients show complete recovery although unremitting complete paralysis or progressive paresis is not uncommon. Severe cases can have overlapping features of CMT type 1. Early diagnosis will allow preventative measures to avoid nerve pressure or trauma to areas such as the elbows, wrists and fibular head.(6)

Electrophysiologic studies show a variable degree of slowing of the NCVs. This slowing, however, is not uniform but more significant across pressure sites such as the fibular head or ulnar groove. Conduction blocks are also seen in many cases, again most commonly at pressure sites. The conduction blocks that may result in HNPP can be confused with acquired neuropathies such as chronic immune demyelinating polyneuropathy.(6) Peripheral nerve biopsies demonstrate the occurrence of focal myelin thickenings called tomacula for "sausage-like". HNPP is sometimes referred to as tomaculous neuropathy.

Also evident on teased fibers are variable internodal lengths and diameters indicating chronic demyelination and remyelination. Some patients also have "onion bulb" formation.

Genetics and Molecular Biology

HNPP is inherited in an autosomal dominant pattern with no confirmed locus heterogeneity. The majority of HNPP cases are caused by deletions of approximately 1.5 megabases of DNA on chromosome 17p11.2-12. This deletion is hypothesized to result from an unequal recombination event during meiosis between repeated stretches of DNA flanking the region. This recombination event results in one gamete with a 1.5 megabase deletion and another with a 1.5 megabase duplication. The duplication is the most common cause of Charcot-Marie-Tooth disease, as described above. This deleted stretch of DNA in HNPP results in a decreased dosage effect of the deleted genes. One of the genes in this region is peripheral myelin protein 22 (PMP22) and the single copy of it (instead of the usual two) or haploinsufficiency is believed to cause the peripheral neuropathy. Mutations that result in loss of function of PMP22, or no available protein from one of the two copies, have also been identified to cause HNPP.

Dejerine-Sottas Syndrome (DSS)

Dejerine-Sottas syndrome was initially described in 1893 by Joseph Jules Dejerine and Jules Sottas.(13) Their initial report was of siblings with presumably unaffected parents making a recessive model of inheritance seem more plausible. Reports since that time, however, are more consistent with a dominant genetic defect.

Clinical Features

DSS is more severe than CMT and usually has an infantile or childhood onset of symptoms. The clinical features overlap with those of CMT type 1. They are, however, more toward the spectrum of congenital hypomyelinating neuropathy. Clubfoot may also be present at birth or children may present with delayed motor milestones and deformity of the feet and lower limbs. Muscle fasciculations usually begin in the legs and progress to other muscles. There may be cranial and spinal nerve involvement leading to nystagmus, miosis, and a Romberg sign. Distal sensory abnormalities usually develop in all four extremities.

Electrophysiologic studies show symmetric and uniform abnormalities. The slowing of the NCVs is greater than in CMT type 1. Cerebrospinal fluid analysis often demonstrates elevated protein.

Peripheral nerve biopsy shows increased size and they are firm and gelatinous. Microscopic examination may show only rare nerve fibers to contain myelin and hypertrophic changes with "onion bulb" formations.

Genetics and Molecular Biology

DSS is inherited in an autosomal dominant pattern with two identified molecular causes and a suspected third locus. Many patients with DSS appear to represent sporadic cases that were believed to be of an autosomal recessive etiology. No molecular studies, however, have demonstrated a recessive DSS.

Molecular genetic studies have shown DSS to be caused by mutations in two of the genes also responsible for CMT type 1. Point mutations and small insertions or deletions have been found in myelin protein zero on chromosome 1q21.2-q33 as a cause of DSS in some patients. Point mutations have been identified in peripheral myelin protein 22 (PMP22) on chromosome 17p11.2 of other patients.(9) There has also been suggestion of an additional locus on chromosome 8q23-q24. However, significant evidence has not been published.(14)

Differential Diagnosis

The disorders described above are readily diagnosed with their classical presentation. Yet, they clearly represent a spectrum and different mutations in the same gene result in different clinical severity and a different diagnosis.(15) With additional symptoms or missing symptoms, however, other inherited and acquired disorders need to be considered in the differential diagnosis.

Acquired Disorders

The recurrent/relapsing course of HNPP can be confused with chronic immune demyelinating polyneuropathy (CIDP). CIDP is considered an autoimmune process diagnosed by focal, asymmetric NCV deficits. The conduction blocks that are seen in CIDP can also be confused with those seen in HNPP. If a peripheral nerve biopsy is done, however, the syndromes can be differentiated because of the lymphocytic infiltrate seen with CIDP as opposed to tomacula seen with HNPP.

Carpal tunnel syndrome is a common acquired nerve entrapment syndrome. Entrapment of the median nerve in the carpal tunnel is often associated with repetitive motion injury and considered purely environmental. The observation of familial carpal tunnel syndrome and two individuals doing the same repetitive task, one of whom gets carpal tunnel syndrome and the other who does not, implies a genetic predisposition. A careful family history of carpal tunnel syndrome patients or molecular analysis may lead to an increased frequency of HNPP diagnoses. HNPP and molecular testing should also be considered in all patients with multifocal neuropathies.(15)

For other, seemingly disease-related acquired neuropathies, such as diabetic neuropathy and alcoholic neuropathy, there may be differences in susceptibility based on genetic polymorphism. With the frequency of CMT in the population, it should be considered as a possible co-morbid state in cases of especially severe or early onset diabetic or toxin induced peripheral neuropathies.

Inherited Disorders

For a disease that appears like CMT, but lacks sensory loss or has only vibratory sensory loss on neurologic examination, a distal form of spinal muscular atrophy (SMA) must be considered [MIM 158590]. There are seven different classifications of SMA with varying age of onset, symptomatology and clinical course. Onset of symptoms for distal hereditary motor neuropathy (SMA IV) is usually in the fourth to sixth decades and both motor and sensory nerve conduction velocities are normal.

If sensory and autonomic symptoms dominate with little motor neuron involvement, two diagnoses should be considered. The first is familial amyloidotic polyneuropathy [MIM 107680, 176300]. This is a heterogeneous disorder with different proteins forming the amyloid deposits. They are inherited in an autosomal dominant pattern and the amyloid deposits are evident on peripheral nerve biopsy. The second diagnosis to consider is hereditary sensory and autonomic neuropathy and similar disorders. Hereditary sensory and autonomic neuropathy type I or hereditary sensory radicular neuropathy [MIM 162400] is inherited in an autosomal dominant pattern and has onset of symptoms between 15-36 years of age.

If ataxia and retinitis pigmentosa are present with a presentation similar to CMT, Refsum disease [MIM 266500] should be considered. In Refsum disease, there is an accumulation of phytanic acid, resulting in the retinal and cerebellar symptoms in addition to the CMT like peripheral neuropathy. Serum phytanic acid measurements will be elevated.

If a static tremor of the hands is present in a clinical setting consistent with CMT, Roussy-Levy hereditary areflexic dystasia [MIM 180800] should be considered. Although this is clinically felt to be a distinct diagnosis, in fact, our experience has been that patients previously diagnosed with Roussy-Levy, when tested, have CMT1A. In addition, 20-30% of CMT patients exhibit tremor. Therefore, this may not be a distinct clinical entity and molecular testing for CMT should be obtained.

If the symptoms are limited to a painful brachial neuropathy, the diagnosis is likely hereditary neuralgic amyotrophy [MIM 162100]. HNPP is much less likely to be limited to the arms and, generally, is not painful even if the brachial plexus is involved. Dysmorphic facies and syndactyly are also, usually, part of hereditary neuralgic amyotrophy.

It should also be remembered that if nerve conduction velocity measurements are normal a muscular dystrophy might be causing the symptoms. Measurements of CPK and a muscle biopsy may be necessary to identify the diagnosis.

Diagnostic Work-Up

1. Detailed history, including age of onset, distribution, progression and type of symptoms, is naturally the first step.
2. This is followed by a careful family history for neurologic symptoms including relatives complaining of difficulty with tripping and spraining ankles or difficulty with snaps, buttons or zippers.
3. Then, a detailed neurologic examination for muscle atrophy, reflexes and sensory changes should be completed.
4. Diagnostic testing should start with measuring nerve conduction velocities (CMT type 1 NCVs are usually below 42 m/sec and 38 m/sec is often used as a cutoff between CMT type 1 and type 2; in HNPP NCVs may be asymmetrically slowed and have conduction blocks; in DSS NCVs are usually below 10 m/sec).

   If CMT type 1 clinically:

   1. FISH or Pulsed-field gel electrophoresis (PFGE)(16) analysis to look for a duplication on chromosome 17 p11.2 (This is the most common cause of CMT, accounting for approximately 70% of CMT type 1.(17)
   2. If normal, and no father to son inheritance is seen in the family, mutation analysis of connexin 32 should be obtained (this is the next most common cause of CMT, accounting for 5-10% of CMT type 1.(17)

   If HNPP clinically:

   1. FISH or PFGE analysis to look for a deletion on chromosome 17p11.2(16) (deletions are detected in 84% of HNPP patients.(17)
5. If a confirmed diagnosis has not been made, perform a peripheral nerve biopsy. Because of the dominant or X-linked inheritance of these disorders once a definitive diagnosis has been made, first degree relatives must be evaluated to clearly define all the family members at risk.