Case 18-2006 — A 57-Year-Old Woman with Numbness and Weakness of the Feet and Legs
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《新英格兰医药杂志》
Presentation of Case
A 57-year-old woman was seen in the neurology clinic of this hospital because of longtime numbness and weakness in her feet and legs.
In adolescence, she had noticed that her pupils were dilated, fixed, and unequal in size. Evaluation at that time did not reveal a cause. She had occasional difficulty seeing in bright light or at night. She did not have orthostatic symptoms. She occasionally had a choking sensation when she swallowed solids or liquids.
When she was in her early 30s, numbness developed over the anterior surfaces of her shins and ankles. She described the sensation as "uncomfortable, burning, and tingling." In her early to mid-40s, she became unsteady when using the stairs or walking in the dark. She noticed weakness in her feet. She had no dorsiflexion of her toes, and they tended to catch on carpets or on thresholds. Her feet occasionally ached, and she believed that her arches had become higher. The numbness worsened and spread to her left lateral thigh. Dysesthetic sensations developed in her feet, which she said felt "cold and wet." She was sometimes unable to tolerate a blanket on her feet. At 47 years of age, she consulted a neurologist at another hospital.
Examination at that time showed fixed, dilated pupils; the left was 8 mm in diameter, and the right 7 mm. Other cranial nerves were normal. Motor strength was 5/5 in the arms, hip flexors, and quadriceps, and on plantar flexion of the feet, but 4/5 on dorsiflexion and eversion of the feet; the toes did not move to dorsiflexion. There was atrophy of the intrinsic foot muscles but not of the legs. She had no talipes cavus. Her blood pressure did not change on sitting or standing. Deep-tendon reflexes were + in the arms and knees; ankle jerks were absent; and plantar reflexes were flexor. There was reduced sensation to pinprick, light touch, vibration, and joint position in both legs below the knees and in both feet. Romberg's sign was present. She had no ataxia of the arms or legs. She could walk on her toes but not on her heels.
Laboratory studies at that time, including routine blood chemical studies, a complete blood count, liver-function tests, a lipid profile, serum protein electrophoresis, antinuclear antibody and rapid plasma reagin tests, erythrocyte sedimentation rate, and levels of vitamin B12, folate, and thyrotropin were normal. The creatine kinase level was reported to be slightly high.
Electromyography at that time showed absent sural and superficial peroneal sensory responses. Median, ulnar, and radial sensory potentials were slightly small with mildly prolonged latencies. Peroneal and tibial motor responses were very small, and conduction velocities were slowed. Median and ulnar motor responses were of normal amplitude, but conduction velocities were mildly slow. Needle examination showed fibrillation potentials in the left extensor hallucis longus and medial gastrocnemius. No fibrillation potentials were seen in the tibialis anterior, vastus lateralis, or muscles in the arms.
During the next 10 years, her gait difficulty progressed gradually. She came to this hospital for further evaluation when she was 57 years of age.
The patient had occasional difficulty with bladder emptying; she had no difficulty chewing or swallowing and no shortness of breath, chest pain, or gastrointestinal symptoms. She thought she had some hearing loss. She occasionally became lightheaded on standing up. She had hypertension that was managed with diuretics. She had had a hysterectomy for fibroids, a cholecystectomy, and a right hemithyroidectomy for a benign tumor.
The father of the patient had had high-arched feet, poor balance, and dilated pupils all his life. In his 50s, numbness and weakness developed in his toes and feet, gradually spread to his knees, and affected his hands; hearing loss, orthostatic hypotension, and impotence developed. When he was 61 years old, an electromyographic study showed evidence of generalized axonal sensorimotor polyneuropathy. Laboratory tests of autonomic reflexes showed reduced heart-rate responses to deep breathing, a reduced Valsalva ratio, persistent sweating activity in the distal lower legs, and no orthostatic hypotension. Examination of a biopsy specimen of his sural nerve revealed moderately reduced myelinated fibers with no onion-bulb formation, inflammatory infiltration, or amyloid.
The patient had five siblings; two brothers had polyneuropathy, one of whom had high-arched feet and hammer toes. The patient had three children. Her 33-year-old son had dilated pupils, her 27-year-old daughter had anisocoria, and her 25-year-old daughter was well.
The patient's vital signs were normal on physical examination. Her blood pressure was 128/88 mm Hg and did not vary with position. The patient had hammer toes but not high-arched feet. No hypertrophic nerves were palpable. Sweating patterns in the palms and axillae were normal. On neurologic examination she was alert and cooperative. She had a head tremor. She walked with forearm crutches. She was unable to walk on her toes or heels. Romberg's sign was present. Her pupils were 6 mm in diameter and unreactive to light or accommodation. Strength in her arms and proximal legs was normal. Strength in the dorsiflexor, invertor, and evertor muscles in the feet was 2/5 bilaterally. Plantar flexor strength was 4/5. Deep-tendon reflexes were absent except for triceps jerks. Sensory examination revealed reduced sensation to light touch in the feet up to the proximal legs and to pinprick to the middle of the legs. Position sense and vibration sensation were absent at the toes and reduced at the ankles. Coordination was normal.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. William J. Triggs: This patient had signs and symptoms of a symmetrical polyneuropathy. The distal predominance of the sensory, motor, and reflex changes demonstrates a disease process in which nerve fibers are affected in a length-dependent manner, with symptoms beginning distally in the feet and toes and progressing proximally over time. Polyneuropathy has an extensive differential diagnosis. However, evaluation of polyneuropathy is typically facilitated by the medical history, neurologic examination, electrodiagnostic studies, and laboratory testing of the patient.
Approach to the Patient with Polyneuropathy
The initial task in the evaluation of polyneuropathy should be consideration of treatable causes by means of appropriate laboratory studies. The most common cause of polyneuropathy in developed countries appears to be diabetes.1 Furthermore, a substantial proportion of patients with idiopathic polyneuropathy who do not have diabetes may have impaired glucose tolerance.2 The cobalamin metabolites methylmalonic acid and homocysteine should be measured if the serum B12 level is in the lower range of the normal limits.3 Evaluation of this patient did not reveal any of these treatable disorders.
Consideration of the temporal progression of polyneuropathy often clarifies the differential diagnosis of the disease.4 For example, acute polyneuropathy, which progresses over a period of days or a few weeks, is most often immune-mediated and probably a variant of the Guillain–Barré syndrome. Subacute polyneuropathy that evolves during a period of months may suggest a toxic or perhaps a metabolic cause for the neuropathy, such as exposure to heavy metals or vitamin B12 deficiency. Chronic polyneuropathy that evolves during a period of years or even decades may be associated with diabetes or monoclonal gammopathy but is more likely to be inherited or idiopathic. The temporal progression of the polyneuropathy of this patient clearly has been chronic and slow. That progression and a strong family history of polyneuropathy point to an inherited pathogenesis.
Charcot–Marie–Tooth Disease
The most common inherited disorder affecting the peripheral nervous system is Charcot–Marie–Tooth disease (also called the Charcot–Marie syndrome), with an estimated prevalence of 1 in 2500 persons.1 This disease is most often an autosomal dominant syndrome characterized by slowly progressive weakness, muscular wasting, and sensory impairment predominantly involving the distal legs.5,6,7 Characteristic physical features include the presence of talipes cavus and hammer toes, presumably reflecting long-term muscular weakness and imbalance between the flexor and extensor muscles of the feet and toes. These findings were present in some family members, but not in the patient. However, Charcot–Marie–Tooth disease is both genetically and phenotypically heterogeneous, and these features are not always evident, so a positive family history may be difficult to document. Furthermore, up to a third of genetic mutations causing this disease are new.8 Other clinical features suggestive of Charcot–Marie–Tooth disease in this patient include a predominance of motor symptoms relative to sensory symptoms and a near absence of positive sensory symptoms, such as a prickling sensation.6
The disorder can be classified according to pathophysiology and inheritance patterns (Table 1).9 The most common form is Charcot–Marie–Tooth disease type 1, followed by type 2. Both are autosomal dominant; type 1 is a demyelinating polyneuropathy, whereas type 2 is an axonal polyneuropathy.7 The vast majority of patients with type 1 have gene mutations affecting peripheral myelin components.10,11,12,13 Charcot–Marie–Tooth disease type 2 is associated with mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, and translation.9,14,15,16,17,18 The onset in adulthood and the autosomal dominant inheritance pattern in this patient's family exclude Charcot–Marie–Tooth disease type 3, type 4, and type X (the X-linked form). Therefore, in all probability, this patient has Charcot–Marie–Tooth disease type 1 or type 2.
Table 1. Pathophysiology and Genetics of Charcot–Marie–Tooth Disease.
Electrodiagnostic Studies
Electrodiagnostic studies (electromyography and nerve conduction studies) are pivotal in the evaluation of polyneuropathy, whether acquired or inherited. They can both confirm the presence of polyneuropathy and, more important, identify the pathophysiology as demyelination or axonal degeneration. Electrodiagnostic studies are used to classify patients as having Charcot–Marie–Tooth disease type 1 (predominantly demyelinating) or type 2 (axonal) on the basis of nerve conduction velocity. Demyelinating neuropathy results in slowing of nerve conduction velocities, which are measured in the largest, fastest-conducting myelinated nerve fibers.19 However, loss of these large myelinated nerve fibers because of axonal degeneration is also associated with some degree of slowing of nerve conduction velocity, but to a lesser extent than in a demyelinating neuropathy, and this slowing is proportional to the degree of axonal loss. Thus, it is necessary to evaluate the degree of slowing of conduction relative to the amount of axonal degeneration that has occurred.20 In practice, nerve conduction velocities less than 80 percent of the lower limit of normal provide evidence of demyelination, provided that substantial axonal loss has not occurred, whereas those between 80 percent and 100 percent of the lower limit of normal are of indeterminate significance. A cutoff for median nerve conduction velocity of 38 m per second (normal, 50 m per second) can be used to distinguish between demyelinating and axonal forms of Charcot–Marie–Tooth disease.7
In this patient, the electrodiagnostic studies showed evidence of axonal degeneration (decreased amplitude of sensory potentials and motor responses and electromyographic evidence of denervation in muscles of the distal leg). Nerve conduction velocities were described as "slowed" in the legs and "mildly slow" in the arms. I will interpret this slowing of conduction as being proportional to the degree of axonal degeneration, not as evidence of demyelination. This interpretation is consistent with several clinical features of this case, including the preservation of the proximal deep-tendon reflexes and the absence of nerve hypertrophy.7 It is also consistent with the electrophysiological and pathological data from the evaluation of the father of the patient. Therefore, I believe this patient has the axonal (neuronal) form of Charcot–Marie–Tooth disease — that is, type 2.
Genetic Subtypes of Charcot–Marie–Tooth Disease Type 2
In contrast to Charcot–Marie–Tooth disease type 1, in which genetic subtypes cannot be distinguished clinically, some of the genetic subtypes of Charcot–Marie–Tooth disease type 2 have some interesting, if not distinguishable, clinical features. For example, poorly healing foot ulcers have been described as a prominent clinical feature in patients with type 2B.21 Diaphragm weakness and vocal-cord paralysis are characteristic of type 2C.22 Type 2D is characterized by weakness and atrophy that is more severe in the hands than in the feet.17
Pupillary dysfunction is a prominent feature of this patient's clinical presentation, which included difficulty seeing in extremes of ambient light. Also, systemic dysautonomia is suggested by symptoms of orthostasis and difficulty with bladder emptying. The patient's father also was noted to have had poorly reactive pupils, as well as orthostatic hypotension and impotence. Two of this patient's children also had pupillary involvement.
In 1998, Marrosu et al.23 reported a Sardinian family with a phenotype of Charcot–Marie–Tooth disease type 2 that was associated with a missense mutation in the myelin protein zero (MPZ) gene. Mutations of this gene had previously been associated with demyelinating Charcot–Marie–Tooth disease type 1B.13 In the past five years, several families with Charcot–Marie–Tooth disease type 2 and mutations in the MPZ gene have been described by other investigators.24,25,26,27,28 Through these reports, a clinically distinctive phenotype of type 2 associated with mutations in the MPZ gene has emerged, characterized by a late-onset axonal polyneuropathy with prominent sensory involvement, pupillary abnormalities, and hearing loss.24,25,26,27,28 The clinical presentation in the case under discussion is consistent with the MPZ phenotype of Charcot–Marie–Tooth disease type 2, including the presence of hearing loss in both the patient and her father.
Sensory Manifestations in Charcot–Marie–Tooth Disease
The sensory manifestations of the polyneuropathy of this patient also merit some discussion. In general, sensory loss in Charcot–Marie–Tooth disease is less severe than is motor dysfunction.6 Furthermore, patients with Charcot–Marie–Tooth disease generally do not have many positive sensory symptoms, such as a prickling sensation. In contrast, the phenotype of Charcot–Marie–Tooth disease type 2 associated with an MPZ gene mutation has been observed to include both marked sensory loss25,26 and prominent pain and paresthesias,25 consistent with the clinical presentation in this case. In conclusion, I believe this patient probably has Charcot–Marie–Tooth disease type 2 associated with an MPZ gene mutation. I believe the diagnostic procedure was a molecular genetic analysis of the MPZ gene.
A Physician: What kind of genetic testing might be undertaken, and with what results?
Dr. Triggs: Genetic testing is commercially available for many of the mutations associated with Charcot–Marie–Tooth disease type 1. In contrast, commercial testing is currently unavailable for most genetic mutations associated with type 2. The syndrome under discussion is one of the few variants of the axonal type 2 phenotype associated with a commercially testable genetic mutation (the MPZ gene). Therefore, even though MPZ gene mutation is a recognized cause of Charcot–Marie–Tooth disease type 1, the assay is also indicated in the evaluation of patients with type 2.
Dr. Nancy Lee Harris (Department of Pathology): Dr. Menkes, would you comment on the definition and physiology of the pupillary abnormality that was seen in this patient?
Dr. Daniel L. Menkes: The pupillary abnormality seen in this patient has been called Adie's pupil. It is characterized by a poor pupillary light reaction, reduced accommodation, sector palsies of the iris, and an enhanced pupillary response to near effort (i.e., attempting to focus on a near object).29 This results in a prolonged, tonic pupillary constriction that is followed by a slow recovery to the original dilated state. The abnormality results from a loss of parasympathetic neurons in the ciliary ganglion, leading to denervation hypersensitivity.30 Pupillary constriction secondary to accommodation is relatively less affected, because the ciliary muscle has innervation that is approximately 30 times as great as that of the iris sphincter. The diagnosis of Adie's pupil can be confirmed by applying a topical ophthalmic solution of 0.1 percent pilocarpine. This will have no effect on a normal or pharmacologically dilated pupil, but will constrict a tonic pupil.
Although most cases of tonic pupil are idiopathic, some have been attributed to trauma, autoimmunity, alcoholism, and herpetic infections. Although most tonic pupils are unilateral, the contralateral eye becomes similarly affected in 15 to 20 percent of cases. When diminished deep-tendon reflexes are associated with a tonic pupil, it is designated the Holmes–Adie syndrome. The diminished reflexes result from dysfunction of the large sensory 1A afferent fibers involved in the spinal reflex arc, which is consistent with an underlying neuropathy.31 One report found that a Tyr145Ser mutation in the MPZ gene resulted in a familial neuropathy with pupillary abnormalities.32 Other, yet-to-be-discovered genetic mutations may also prove responsible for the Holmes–Adie syndrome.
Dr. Harris: Dr. Cros, would you summarize your thinking before the diagnostic test?
Dr. Didier P. Cros (Department of Neurology): I thought the patient had an autosomal dominant axonal polyneuropathy consistent with Charcot–Marie–Tooth disease type 2, with the unusual association of a pupillary abnormality and hearing loss. I sent peripheral-blood leukocytes for analysis of the MPZ gene.
Clinical Diagnosis
Charcot–Marie–Tooth disease type 2.
Dr. William J. Triggs's Diagnosis
Charcot–Marie–Tooth disease type 2, associated with an MPZ gene mutation.
Pathological Discussion
Dr. Robert H. Brown, Jr.: The diagnostic study was analysis of the MPZ gene. As predicted, it documented the presence of a mutation — cytosine to thymidine at base pair 371 (C371T) — which resulted in changing threonine to methionine at amino acid residue 124 (T124M) (Figure 1).
Figure 1. Mutations in the Open Reading Frame of the Myelin Protein Zero (MPZ) Gene Associated with Inherited Neuropathy.
Adhesive interface, fourfold interface, and head-to-head interface refer to amino acid residues deemed essential for cis and trans adhesion between adjacent myelin wraps. The numbering system for MPZ mutations does not include the leader peptide of 29 amino acids cleaved before insertion into the myelin sheath. The mutation found in this patient is shown with an arrowhead. (Adapted from Shy et al.33 with the permission of the publisher.)
There has been dramatic progress during the past 10 years in the molecular analysis of inheritable peripheral neuropathies. Many of the proteins that have been implicated in these diseases are components of myelin. Myelin protein zero is a member of the immunoglobulin superfamily, with distinct extracellular, transmembrane, and intracellular domains (Figure 1). It may be important not only in forming myelin but also in cell signaling. Myelin protein zero forms homotetramers that adhere to one another with high affinity and may span two membranes, holding them together and compacting the myelin (Figure 2).
Figure 2. Structure and Function of the Myelin Protein Zero (MPZ) Gene.
Myelin protein zero is a member of the immunoglobulin superfamily. It has distinct extracellular, transmembrane, and intracellular domains (Panel A). It has 218 amino acids — an initial 29 amino acids cleaved before insertion into the membrane, an immunoglobulin-like extracellular domain containing 124 amino acids, a transmembrane domain containing 25 amino acids, and a cytoplasmic domain of 69 amino acids. It is post-translationally modified to add a single oligosaccharide in the extracellular domain and many other groups (e.g., sulfate, acyl, and phosphate). Myelin protein zero forms homotetrameric structures (Panel B), which in turn form homophilic bonds across the extracellular space. In essence, myelin protein zero functions as an adhesion molecule by forming doughnut-like homotetramers within the plane of the membrane. These interact homophilically with an analogous doughnut on the opposite membrane to provide intermembrane adhesion. The latter is essential for compaction of myelin; mice lacking myelin protein zero show early failure of membrane compaction. Activity of the cytoplasmic domain (and a protein kinase C domain) is necessary for the adhesive properties of myelin protein zero. It also functions in the regulation of myelinogenesis, through a myelin protein zero–triggered signal cascade. Mutations that affect the adhesive function produce severe, early-onset neuropathy, whereas those that affect the signaling function are associated with milder, late-onset disease.
Patients with MPZ mutations fall into the following two major categories: those with onset of neuropathy in infancy and those with onset in adulthood.28,33 The conduction velocities are subnormal in all cases, but there is more profound slowing in patients with early-onset disease than in those with late-onset disease. Major myelin disturbance is seen pathologically in the early group and axonal disturbance in the late group. More than 95 mutations have been described, most affecting the extracellular domain of the protein, and the types of mutations are different in early-onset as compared with late-onset cases. In general, the mutations found in early-onset cases are predicted to have a much more profound effect on the protein, whereas those found in the late-onset cases produce more subtle structural alterations (for the mutation database of inherited peripheral neuropathies, see www.molgen.ua.ac.be/CMTMutations/). The mutations seen in early-onset cases are associated with major impairment in the compacting of myelin, whereas the changes predicted by the mutations seen in late-onset cases appear to disrupt signaling and myelinogenesis but do not cause a fundamental problem with myelin compacting.34
The threonine-to-methionine mutation is characteristic of late-onset cases, as was seen in this patient and her family. Many of the features present in this family are reported in other families with this mutation. In addition to axonal peripheral neuropathy, many of the patients have autonomic dysfunction, deafness, and pupillary abnormalities (e.g., Adie's pupil).
Mouse models of inherited neuropathies suggest that there may be an immunologic component to the progression of the neurologic disease.35 Several reports suggest that high-dose corticosteroid use can slow disease progression in patients with MPZ mutations.36
Anatomical Diagnosis
Charcot–Marie–Tooth disease type 2, with Adie's pupil and a mutation in the MPZ gene.
Dr. Brown reports having received consulting fees from CytRx, Biogen Idec, and Acceleron Pharma, as well as research funding from CytRx from 2003 to 2005. Dr. Menkes reports having received a founders grant from the Neuropathy Research Foundation to initiate research at his institution. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Neurology, McKnight Brain Institute, University of Florida, and the University of Florida College of Medicine — both in Gainesville (W.J.T.); the Department of Neurology, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School — both in Boston (R.H.B.); and the Department of Neurology, University of Tennessee Health Sciences Center, Memphis (D.L.M.).
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A 57-year-old woman was seen in the neurology clinic of this hospital because of longtime numbness and weakness in her feet and legs.
In adolescence, she had noticed that her pupils were dilated, fixed, and unequal in size. Evaluation at that time did not reveal a cause. She had occasional difficulty seeing in bright light or at night. She did not have orthostatic symptoms. She occasionally had a choking sensation when she swallowed solids or liquids.
When she was in her early 30s, numbness developed over the anterior surfaces of her shins and ankles. She described the sensation as "uncomfortable, burning, and tingling." In her early to mid-40s, she became unsteady when using the stairs or walking in the dark. She noticed weakness in her feet. She had no dorsiflexion of her toes, and they tended to catch on carpets or on thresholds. Her feet occasionally ached, and she believed that her arches had become higher. The numbness worsened and spread to her left lateral thigh. Dysesthetic sensations developed in her feet, which she said felt "cold and wet." She was sometimes unable to tolerate a blanket on her feet. At 47 years of age, she consulted a neurologist at another hospital.
Examination at that time showed fixed, dilated pupils; the left was 8 mm in diameter, and the right 7 mm. Other cranial nerves were normal. Motor strength was 5/5 in the arms, hip flexors, and quadriceps, and on plantar flexion of the feet, but 4/5 on dorsiflexion and eversion of the feet; the toes did not move to dorsiflexion. There was atrophy of the intrinsic foot muscles but not of the legs. She had no talipes cavus. Her blood pressure did not change on sitting or standing. Deep-tendon reflexes were + in the arms and knees; ankle jerks were absent; and plantar reflexes were flexor. There was reduced sensation to pinprick, light touch, vibration, and joint position in both legs below the knees and in both feet. Romberg's sign was present. She had no ataxia of the arms or legs. She could walk on her toes but not on her heels.
Laboratory studies at that time, including routine blood chemical studies, a complete blood count, liver-function tests, a lipid profile, serum protein electrophoresis, antinuclear antibody and rapid plasma reagin tests, erythrocyte sedimentation rate, and levels of vitamin B12, folate, and thyrotropin were normal. The creatine kinase level was reported to be slightly high.
Electromyography at that time showed absent sural and superficial peroneal sensory responses. Median, ulnar, and radial sensory potentials were slightly small with mildly prolonged latencies. Peroneal and tibial motor responses were very small, and conduction velocities were slowed. Median and ulnar motor responses were of normal amplitude, but conduction velocities were mildly slow. Needle examination showed fibrillation potentials in the left extensor hallucis longus and medial gastrocnemius. No fibrillation potentials were seen in the tibialis anterior, vastus lateralis, or muscles in the arms.
During the next 10 years, her gait difficulty progressed gradually. She came to this hospital for further evaluation when she was 57 years of age.
The patient had occasional difficulty with bladder emptying; she had no difficulty chewing or swallowing and no shortness of breath, chest pain, or gastrointestinal symptoms. She thought she had some hearing loss. She occasionally became lightheaded on standing up. She had hypertension that was managed with diuretics. She had had a hysterectomy for fibroids, a cholecystectomy, and a right hemithyroidectomy for a benign tumor.
The father of the patient had had high-arched feet, poor balance, and dilated pupils all his life. In his 50s, numbness and weakness developed in his toes and feet, gradually spread to his knees, and affected his hands; hearing loss, orthostatic hypotension, and impotence developed. When he was 61 years old, an electromyographic study showed evidence of generalized axonal sensorimotor polyneuropathy. Laboratory tests of autonomic reflexes showed reduced heart-rate responses to deep breathing, a reduced Valsalva ratio, persistent sweating activity in the distal lower legs, and no orthostatic hypotension. Examination of a biopsy specimen of his sural nerve revealed moderately reduced myelinated fibers with no onion-bulb formation, inflammatory infiltration, or amyloid.
The patient had five siblings; two brothers had polyneuropathy, one of whom had high-arched feet and hammer toes. The patient had three children. Her 33-year-old son had dilated pupils, her 27-year-old daughter had anisocoria, and her 25-year-old daughter was well.
The patient's vital signs were normal on physical examination. Her blood pressure was 128/88 mm Hg and did not vary with position. The patient had hammer toes but not high-arched feet. No hypertrophic nerves were palpable. Sweating patterns in the palms and axillae were normal. On neurologic examination she was alert and cooperative. She had a head tremor. She walked with forearm crutches. She was unable to walk on her toes or heels. Romberg's sign was present. Her pupils were 6 mm in diameter and unreactive to light or accommodation. Strength in her arms and proximal legs was normal. Strength in the dorsiflexor, invertor, and evertor muscles in the feet was 2/5 bilaterally. Plantar flexor strength was 4/5. Deep-tendon reflexes were absent except for triceps jerks. Sensory examination revealed reduced sensation to light touch in the feet up to the proximal legs and to pinprick to the middle of the legs. Position sense and vibration sensation were absent at the toes and reduced at the ankles. Coordination was normal.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. William J. Triggs: This patient had signs and symptoms of a symmetrical polyneuropathy. The distal predominance of the sensory, motor, and reflex changes demonstrates a disease process in which nerve fibers are affected in a length-dependent manner, with symptoms beginning distally in the feet and toes and progressing proximally over time. Polyneuropathy has an extensive differential diagnosis. However, evaluation of polyneuropathy is typically facilitated by the medical history, neurologic examination, electrodiagnostic studies, and laboratory testing of the patient.
Approach to the Patient with Polyneuropathy
The initial task in the evaluation of polyneuropathy should be consideration of treatable causes by means of appropriate laboratory studies. The most common cause of polyneuropathy in developed countries appears to be diabetes.1 Furthermore, a substantial proportion of patients with idiopathic polyneuropathy who do not have diabetes may have impaired glucose tolerance.2 The cobalamin metabolites methylmalonic acid and homocysteine should be measured if the serum B12 level is in the lower range of the normal limits.3 Evaluation of this patient did not reveal any of these treatable disorders.
Consideration of the temporal progression of polyneuropathy often clarifies the differential diagnosis of the disease.4 For example, acute polyneuropathy, which progresses over a period of days or a few weeks, is most often immune-mediated and probably a variant of the Guillain–Barré syndrome. Subacute polyneuropathy that evolves during a period of months may suggest a toxic or perhaps a metabolic cause for the neuropathy, such as exposure to heavy metals or vitamin B12 deficiency. Chronic polyneuropathy that evolves during a period of years or even decades may be associated with diabetes or monoclonal gammopathy but is more likely to be inherited or idiopathic. The temporal progression of the polyneuropathy of this patient clearly has been chronic and slow. That progression and a strong family history of polyneuropathy point to an inherited pathogenesis.
Charcot–Marie–Tooth Disease
The most common inherited disorder affecting the peripheral nervous system is Charcot–Marie–Tooth disease (also called the Charcot–Marie syndrome), with an estimated prevalence of 1 in 2500 persons.1 This disease is most often an autosomal dominant syndrome characterized by slowly progressive weakness, muscular wasting, and sensory impairment predominantly involving the distal legs.5,6,7 Characteristic physical features include the presence of talipes cavus and hammer toes, presumably reflecting long-term muscular weakness and imbalance between the flexor and extensor muscles of the feet and toes. These findings were present in some family members, but not in the patient. However, Charcot–Marie–Tooth disease is both genetically and phenotypically heterogeneous, and these features are not always evident, so a positive family history may be difficult to document. Furthermore, up to a third of genetic mutations causing this disease are new.8 Other clinical features suggestive of Charcot–Marie–Tooth disease in this patient include a predominance of motor symptoms relative to sensory symptoms and a near absence of positive sensory symptoms, such as a prickling sensation.6
The disorder can be classified according to pathophysiology and inheritance patterns (Table 1).9 The most common form is Charcot–Marie–Tooth disease type 1, followed by type 2. Both are autosomal dominant; type 1 is a demyelinating polyneuropathy, whereas type 2 is an axonal polyneuropathy.7 The vast majority of patients with type 1 have gene mutations affecting peripheral myelin components.10,11,12,13 Charcot–Marie–Tooth disease type 2 is associated with mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, and translation.9,14,15,16,17,18 The onset in adulthood and the autosomal dominant inheritance pattern in this patient's family exclude Charcot–Marie–Tooth disease type 3, type 4, and type X (the X-linked form). Therefore, in all probability, this patient has Charcot–Marie–Tooth disease type 1 or type 2.
Table 1. Pathophysiology and Genetics of Charcot–Marie–Tooth Disease.
Electrodiagnostic Studies
Electrodiagnostic studies (electromyography and nerve conduction studies) are pivotal in the evaluation of polyneuropathy, whether acquired or inherited. They can both confirm the presence of polyneuropathy and, more important, identify the pathophysiology as demyelination or axonal degeneration. Electrodiagnostic studies are used to classify patients as having Charcot–Marie–Tooth disease type 1 (predominantly demyelinating) or type 2 (axonal) on the basis of nerve conduction velocity. Demyelinating neuropathy results in slowing of nerve conduction velocities, which are measured in the largest, fastest-conducting myelinated nerve fibers.19 However, loss of these large myelinated nerve fibers because of axonal degeneration is also associated with some degree of slowing of nerve conduction velocity, but to a lesser extent than in a demyelinating neuropathy, and this slowing is proportional to the degree of axonal loss. Thus, it is necessary to evaluate the degree of slowing of conduction relative to the amount of axonal degeneration that has occurred.20 In practice, nerve conduction velocities less than 80 percent of the lower limit of normal provide evidence of demyelination, provided that substantial axonal loss has not occurred, whereas those between 80 percent and 100 percent of the lower limit of normal are of indeterminate significance. A cutoff for median nerve conduction velocity of 38 m per second (normal, 50 m per second) can be used to distinguish between demyelinating and axonal forms of Charcot–Marie–Tooth disease.7
In this patient, the electrodiagnostic studies showed evidence of axonal degeneration (decreased amplitude of sensory potentials and motor responses and electromyographic evidence of denervation in muscles of the distal leg). Nerve conduction velocities were described as "slowed" in the legs and "mildly slow" in the arms. I will interpret this slowing of conduction as being proportional to the degree of axonal degeneration, not as evidence of demyelination. This interpretation is consistent with several clinical features of this case, including the preservation of the proximal deep-tendon reflexes and the absence of nerve hypertrophy.7 It is also consistent with the electrophysiological and pathological data from the evaluation of the father of the patient. Therefore, I believe this patient has the axonal (neuronal) form of Charcot–Marie–Tooth disease — that is, type 2.
Genetic Subtypes of Charcot–Marie–Tooth Disease Type 2
In contrast to Charcot–Marie–Tooth disease type 1, in which genetic subtypes cannot be distinguished clinically, some of the genetic subtypes of Charcot–Marie–Tooth disease type 2 have some interesting, if not distinguishable, clinical features. For example, poorly healing foot ulcers have been described as a prominent clinical feature in patients with type 2B.21 Diaphragm weakness and vocal-cord paralysis are characteristic of type 2C.22 Type 2D is characterized by weakness and atrophy that is more severe in the hands than in the feet.17
Pupillary dysfunction is a prominent feature of this patient's clinical presentation, which included difficulty seeing in extremes of ambient light. Also, systemic dysautonomia is suggested by symptoms of orthostasis and difficulty with bladder emptying. The patient's father also was noted to have had poorly reactive pupils, as well as orthostatic hypotension and impotence. Two of this patient's children also had pupillary involvement.
In 1998, Marrosu et al.23 reported a Sardinian family with a phenotype of Charcot–Marie–Tooth disease type 2 that was associated with a missense mutation in the myelin protein zero (MPZ) gene. Mutations of this gene had previously been associated with demyelinating Charcot–Marie–Tooth disease type 1B.13 In the past five years, several families with Charcot–Marie–Tooth disease type 2 and mutations in the MPZ gene have been described by other investigators.24,25,26,27,28 Through these reports, a clinically distinctive phenotype of type 2 associated with mutations in the MPZ gene has emerged, characterized by a late-onset axonal polyneuropathy with prominent sensory involvement, pupillary abnormalities, and hearing loss.24,25,26,27,28 The clinical presentation in the case under discussion is consistent with the MPZ phenotype of Charcot–Marie–Tooth disease type 2, including the presence of hearing loss in both the patient and her father.
Sensory Manifestations in Charcot–Marie–Tooth Disease
The sensory manifestations of the polyneuropathy of this patient also merit some discussion. In general, sensory loss in Charcot–Marie–Tooth disease is less severe than is motor dysfunction.6 Furthermore, patients with Charcot–Marie–Tooth disease generally do not have many positive sensory symptoms, such as a prickling sensation. In contrast, the phenotype of Charcot–Marie–Tooth disease type 2 associated with an MPZ gene mutation has been observed to include both marked sensory loss25,26 and prominent pain and paresthesias,25 consistent with the clinical presentation in this case. In conclusion, I believe this patient probably has Charcot–Marie–Tooth disease type 2 associated with an MPZ gene mutation. I believe the diagnostic procedure was a molecular genetic analysis of the MPZ gene.
A Physician: What kind of genetic testing might be undertaken, and with what results?
Dr. Triggs: Genetic testing is commercially available for many of the mutations associated with Charcot–Marie–Tooth disease type 1. In contrast, commercial testing is currently unavailable for most genetic mutations associated with type 2. The syndrome under discussion is one of the few variants of the axonal type 2 phenotype associated with a commercially testable genetic mutation (the MPZ gene). Therefore, even though MPZ gene mutation is a recognized cause of Charcot–Marie–Tooth disease type 1, the assay is also indicated in the evaluation of patients with type 2.
Dr. Nancy Lee Harris (Department of Pathology): Dr. Menkes, would you comment on the definition and physiology of the pupillary abnormality that was seen in this patient?
Dr. Daniel L. Menkes: The pupillary abnormality seen in this patient has been called Adie's pupil. It is characterized by a poor pupillary light reaction, reduced accommodation, sector palsies of the iris, and an enhanced pupillary response to near effort (i.e., attempting to focus on a near object).29 This results in a prolonged, tonic pupillary constriction that is followed by a slow recovery to the original dilated state. The abnormality results from a loss of parasympathetic neurons in the ciliary ganglion, leading to denervation hypersensitivity.30 Pupillary constriction secondary to accommodation is relatively less affected, because the ciliary muscle has innervation that is approximately 30 times as great as that of the iris sphincter. The diagnosis of Adie's pupil can be confirmed by applying a topical ophthalmic solution of 0.1 percent pilocarpine. This will have no effect on a normal or pharmacologically dilated pupil, but will constrict a tonic pupil.
Although most cases of tonic pupil are idiopathic, some have been attributed to trauma, autoimmunity, alcoholism, and herpetic infections. Although most tonic pupils are unilateral, the contralateral eye becomes similarly affected in 15 to 20 percent of cases. When diminished deep-tendon reflexes are associated with a tonic pupil, it is designated the Holmes–Adie syndrome. The diminished reflexes result from dysfunction of the large sensory 1A afferent fibers involved in the spinal reflex arc, which is consistent with an underlying neuropathy.31 One report found that a Tyr145Ser mutation in the MPZ gene resulted in a familial neuropathy with pupillary abnormalities.32 Other, yet-to-be-discovered genetic mutations may also prove responsible for the Holmes–Adie syndrome.
Dr. Harris: Dr. Cros, would you summarize your thinking before the diagnostic test?
Dr. Didier P. Cros (Department of Neurology): I thought the patient had an autosomal dominant axonal polyneuropathy consistent with Charcot–Marie–Tooth disease type 2, with the unusual association of a pupillary abnormality and hearing loss. I sent peripheral-blood leukocytes for analysis of the MPZ gene.
Clinical Diagnosis
Charcot–Marie–Tooth disease type 2.
Dr. William J. Triggs's Diagnosis
Charcot–Marie–Tooth disease type 2, associated with an MPZ gene mutation.
Pathological Discussion
Dr. Robert H. Brown, Jr.: The diagnostic study was analysis of the MPZ gene. As predicted, it documented the presence of a mutation — cytosine to thymidine at base pair 371 (C371T) — which resulted in changing threonine to methionine at amino acid residue 124 (T124M) (Figure 1).
Figure 1. Mutations in the Open Reading Frame of the Myelin Protein Zero (MPZ) Gene Associated with Inherited Neuropathy.
Adhesive interface, fourfold interface, and head-to-head interface refer to amino acid residues deemed essential for cis and trans adhesion between adjacent myelin wraps. The numbering system for MPZ mutations does not include the leader peptide of 29 amino acids cleaved before insertion into the myelin sheath. The mutation found in this patient is shown with an arrowhead. (Adapted from Shy et al.33 with the permission of the publisher.)
There has been dramatic progress during the past 10 years in the molecular analysis of inheritable peripheral neuropathies. Many of the proteins that have been implicated in these diseases are components of myelin. Myelin protein zero is a member of the immunoglobulin superfamily, with distinct extracellular, transmembrane, and intracellular domains (Figure 1). It may be important not only in forming myelin but also in cell signaling. Myelin protein zero forms homotetramers that adhere to one another with high affinity and may span two membranes, holding them together and compacting the myelin (Figure 2).
Figure 2. Structure and Function of the Myelin Protein Zero (MPZ) Gene.
Myelin protein zero is a member of the immunoglobulin superfamily. It has distinct extracellular, transmembrane, and intracellular domains (Panel A). It has 218 amino acids — an initial 29 amino acids cleaved before insertion into the membrane, an immunoglobulin-like extracellular domain containing 124 amino acids, a transmembrane domain containing 25 amino acids, and a cytoplasmic domain of 69 amino acids. It is post-translationally modified to add a single oligosaccharide in the extracellular domain and many other groups (e.g., sulfate, acyl, and phosphate). Myelin protein zero forms homotetrameric structures (Panel B), which in turn form homophilic bonds across the extracellular space. In essence, myelin protein zero functions as an adhesion molecule by forming doughnut-like homotetramers within the plane of the membrane. These interact homophilically with an analogous doughnut on the opposite membrane to provide intermembrane adhesion. The latter is essential for compaction of myelin; mice lacking myelin protein zero show early failure of membrane compaction. Activity of the cytoplasmic domain (and a protein kinase C domain) is necessary for the adhesive properties of myelin protein zero. It also functions in the regulation of myelinogenesis, through a myelin protein zero–triggered signal cascade. Mutations that affect the adhesive function produce severe, early-onset neuropathy, whereas those that affect the signaling function are associated with milder, late-onset disease.
Patients with MPZ mutations fall into the following two major categories: those with onset of neuropathy in infancy and those with onset in adulthood.28,33 The conduction velocities are subnormal in all cases, but there is more profound slowing in patients with early-onset disease than in those with late-onset disease. Major myelin disturbance is seen pathologically in the early group and axonal disturbance in the late group. More than 95 mutations have been described, most affecting the extracellular domain of the protein, and the types of mutations are different in early-onset as compared with late-onset cases. In general, the mutations found in early-onset cases are predicted to have a much more profound effect on the protein, whereas those found in the late-onset cases produce more subtle structural alterations (for the mutation database of inherited peripheral neuropathies, see www.molgen.ua.ac.be/CMTMutations/). The mutations seen in early-onset cases are associated with major impairment in the compacting of myelin, whereas the changes predicted by the mutations seen in late-onset cases appear to disrupt signaling and myelinogenesis but do not cause a fundamental problem with myelin compacting.34
The threonine-to-methionine mutation is characteristic of late-onset cases, as was seen in this patient and her family. Many of the features present in this family are reported in other families with this mutation. In addition to axonal peripheral neuropathy, many of the patients have autonomic dysfunction, deafness, and pupillary abnormalities (e.g., Adie's pupil).
Mouse models of inherited neuropathies suggest that there may be an immunologic component to the progression of the neurologic disease.35 Several reports suggest that high-dose corticosteroid use can slow disease progression in patients with MPZ mutations.36
Anatomical Diagnosis
Charcot–Marie–Tooth disease type 2, with Adie's pupil and a mutation in the MPZ gene.
Dr. Brown reports having received consulting fees from CytRx, Biogen Idec, and Acceleron Pharma, as well as research funding from CytRx from 2003 to 2005. Dr. Menkes reports having received a founders grant from the Neuropathy Research Foundation to initiate research at his institution. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Neurology, McKnight Brain Institute, University of Florida, and the University of Florida College of Medicine — both in Gainesville (W.J.T.); the Department of Neurology, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School — both in Boston (R.H.B.); and the Department of Neurology, University of Tennessee Health Sciences Center, Memphis (D.L.M.).
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