CMT is a clinically and genetically heterogeneous group of hereditary sensorimotor neuropathies characterized by slowly progressive, primarily distal limb weakness, atrophy, and sensory loss. Over 12 genetic loci, or genes, are known, some associated with more than one phenotype. CMT1, characterized by severely and uniformly slowed nerve conduction velocities and primary hypertrophic myelin pathology with prominent onion bulbs and secondary axonal changes, is at least twice as common as CMT2, the nondemyelinating neuronal type with relatively normal nerve conduction velocities and primary axonal pathology. While in the neuronal form nerves are not enlarged, weakness may be milder and onset is later, the distinction is difficult to make in individual patients by history and exam alone. Due to the non-specific electrical findings, later onset and milder symptoms, it may be very difficult to make a CMT2 diagnosis without a clear family history. We recently examined over 20 relatives with an autosomal dominant neuronal neuropathy. While motor symptoms predominated, sensory and motor signs were equally prominent. Nerves were not enlarged. In adults calf atrophy, high arches, and Achilles tendon shortening were seen (Figure 1A, B), as was tremor, but hammer toes were rare. Age of onset was in the first decade. Motor nerve conduction velocities were typically between 30 and 40 m/s. Nerve biopsies demonstrated a reduction in large myelinated fibers; teased fibers revealed no primary myelin abnormalities. No MPZ or Cx32 mutation or PMP22 duplication was found. However, currently PMP22 and EGR2 sequencing is in progress. Gene linkage studies are also under way to identify the chromosome region that may harbor a candidate gene for CMT in this family.
This case study provided courtesy of K. Florian P. Thomas, MD of St. Louis University, St. Louis, Missouri
The proband (PN-27.1) had no family history of any neuromuscular disorder and his parents were not consanguineous. His three brothers and sister were healthy on clinical diagnosis. The patient's birth was normal, but he had some breathing and feeding difficulties in the first weeks of postnatal life. His head tended to fall to one side and he never crawled. Other motor milestones were delayed and he could not walk without support until the age of three years. At the age of four years, he had difficulties standing and walking, tended to fall often, and needed help to rise from a sitting position. His intellectual milestones were normal and he started to speak at one year of age. Clinical examination at six years of age revealed that he tended to walk with a broad base. He was unable to get up from a supine position. The neck muscles were moderately weak and there was mild facial weakness. The limb muscles were very weak and atrophic. The tendon reflexes were absent and the plantar reflexes were flexor. Sensation, as far as it could be tested, was normal. The motor NCVs of the median and fibular nerve were 8 m/s and the amplitudes of the evoked motor responses were severely reduced. The sensory nerve action potentials could not be elicited. The patient's father (PN-27.2) and mother (PN-27.3) had normal motor median NCVs of 59 and 55m/s, respectively. Sural nerve biopsy of patient PN-27.1 demonstrated onion bulb formation. Each onion bulb contained either a demyelinating axon with increased density of neurofilaments and neurotubules, a remyelinated axon, or, less frequently, a normal myelinated axon. Focally folded myelin sheaths were found with redundant myelin loops and excessive myelin infolding and outfolding, not wrapping the entire axon.
Molecular analysis of patient PN-27.1 showed a de novo mutation in the early growth response 2 gene (EGR2), which was not present in the healthy parents of the patient, and the patient was diagnosed with Dejerine-Sottas syndrome. Patient PN-27.1 died at the age of 16 years from respiratory failure associated with pulmonary infection.
Figure 1. NlaIII restriction pattern of the EGR2 ARG359Trp mutation in family PN-27. In the normal control (C), PN-27.2 (father) and PN-27.3 (mother), two PCR fragments are obtained of 159 and 25 bp. In the patient with de novo Dejerine-Sottas syndrome, PN-27.1, the 107-and 52-bp fragments result from an additional NlaIII restriction site due to the Arg359Trp mutation. The size marker (M) represents a 100-bp ladder (Gibco BRL-Life Technologies). The total length of the EGR2 PCR product amplified with primers 2.5cF and 2.5cR is 184 bp.
Reprinted with permission from Neurology 1999; 52:1827-1832. By Lippincott Williams & Wilkins. http://www.lww.com
A 45-year-old woman complained of progressive weakness in her lower extremities. She was the product of a normal pregnancy and delivery. She reached early milestones such as sitting and walking at normal ages. As a young child, she participated in all the typical childhood games with her friends. However, she noted that she was the slowest runner in her third grade class, that she had difficulty learning to ride a bike, and that she was never able to ice skate. Her hands did not bother her in childhood. Her foot troubles slowly progressed through her teenage years, and in her late teens, surgery was considered in order to stabilize her ankles. In her late 20s, she began wearing ankle-foot orthoses on both feet. At about this time, she began to notice mild difficulties opening jars and writing for long periods, although she could normally perform movements such as buttoning clothes or operating zippers. Balance had always been a problem for her. Temperature and pain sensation had been relatively normal until approximately one or two years prior to her office visit. During this period she had noticed that when she walked barefoot it seemed like she was "walking on pebbles," and when she placed her feet in bath water, the water would feel alright for her feet, but would burn her calves. Her feet would easily turn cold and become discolored. Otherwise she had no symptoms of autonomic abnormality. Bladder and bowel functions were normal. Her thought processes had remained entirely normal. She had no evidence of diabetes mellitus or other systemic disorders.
The patient had a positive family history of foot problems. Her father had mild difficulties with both feet at an older age and needed to wear orthotics to stabilize his ankles. His father (her paternal grandfather) was noted to have been clumsy and not a good athlete. The patient's daughter had developed foot problems as a teenager; her two sons had no difficulties with feet or hands.
Neurologic examination Mental status and cranial nerve examinations were entirely normal. On motor examination, there was significant wasting in the intrinsic hand muscles bilaterally. She also had prominent distal wasting of both calves and bilateral pes cavus. Muscle tone was normal. In her upper extremities, strength to confrontation was full in her deltoids, biceps, triceps, wrist extensors, wrist flexors, and finger flexors. Finger extensors were graded as 4+/5 bilaterally, first dorsal interosseous muscles 4/5, and abductor pollicis brevis muscles 4/5. In her lower extremities, iliopsoas, quadriceps, hamstrings, abductors, adductors, and gastrocnemii were 5/5. Both anterior tibialis and both peroneus longus/brevis muscles were 4+/5, and both extensor hallucis longus muscles were 4/5.
On sensory examination, she had a decrease to cold and pinprick sensation in a stocking distribution halfway up her calves and in a glove distribution up to her wrists. She could not feel vibration from a 128 Hz tuning fork in either great toe, and vibration was reduced in her distal, but not proximal, fingers.
She was areflexic and did not have Babinski signs. Although she could walk 25 feet in less than 10 seconds, her gait was mildly abnormal with a steppage quality. She could walk on her tiptoes, but not on her heels. Her tandem gait was poor, and she was unsteady when performing a Romberg maneuver.
Diagnostic tests Nerve conduction velocities were performed, revealing uniformly slowed motor nerve conduction velocities in the upper extremities with velocities of 20 m/sec and prolonged distal motor and F-wave latencies. Peroneal and tibial motor conductions were unobtainable with surface recording at the EDP and abductor digiti minimi muscles, respectively. Peroneal conductions with recording at the anterior tibialis muscle gave a value of 20 m/sec. Compound muscle action potentials were normal in the upper extremities. Sensory nerve action potentials were unobtainable for median, ulnar, and sural nerves.
Because of the positive family history, typical clinical examination, and uniformly slowed nerve conduction velocities, genetic testing was obtained from a blood sample. Results demonstrated a duplication of one of the peripheral myelin protein 22 kD (PMP22) alleles on chromosome 17. A diagnosis of Charcot-Marie-Tooth type 1A was made.
Management Because of continuing difficulties with her gait, the patient was evaluated by a physiatrist with particular expertise in treating neuromuscular disease. It was found that neither of her ankle-foot orthoses fit appropriately, and adjustments were made on both.
Because she had questions concerning hereditary risk and wanted to be informed of options with respect to future transmission of the disease, she met with a genetic counselor familiar with Charcot-Marie-Tooth disease. Because she also had concerns about the natural history of the disease, she met with her neurologist in addition to the genetic counselor.
Course of disease There was no obvious evidence of disease progression in the two years of follow-up after her initial evaluation. Her ability to ambulate improved with the new ankle-foot orthoses, and the fatigue she had been experiencing was reduced.
Shy M.E. and Kamholz J. Charcot-Marie-Tooth-type hereditary neuropathies. In: MedLink-Neurobase (www.medlink.com), 2nd ed., ed. S. Gilman. 2000. San Diego: Arbor Publishing.
The patient (1006) was initially referred for a genetics consultation at age 12 years when a chromosome analysis (performed because of short stature and growth hormone deficiency) revealed an apparent duplication of bands p11.2p12 in one chromosome 17. Reevaluation at age 14 years was prompted by the patient's worsening clinical status, characterized by increasing hand and lower-leg fatigue; muscle weakness of the hands, lower legs, and feet; and progressive pes cavus deformity of the left foot.
The patient, weighing 6 pounds, 2 ounces at birth, was delivered vaginally to a 27-year-old primigravida whose pregnancy was normal and full term. The neonatal period was complicated by a spontaneous pneumothorax, which necessitated mechanical ventilation, and a left club-foot deformity, which required casting until age 13 months and corrective surgery at age 14 months. A right metatarsus adductus was noted in infancy and required splinting. Developmentally, the patient sat independently at 6 1/2 months, crawled at 9 months, walked with assistance at 14 months, and walked independently at 19 months. Delayed speech and poor articulation necessitated speech therapy, which was instituted by age 3 years. Attention deficit was diagnosed at age 7 years and Ritalin was prescribed. Formal developmental testing at age 12 years revealed a full-scale IQ of 62, verbal scale IQ of 75, and performance scale of 53 (Wechsler Intelligence Scale for Children). Short stature was noted at age 10-11 years. Evaluation revealed growth hormone deficiency with a normal pituitary gland. The patient currently receives daily growth hormone injections. Other medical history includes episodic microscopic hematuria, hyperopia, and dental malocclusion.
Significant findings on physical examination at age 14 years include height at the 7th percentile; occipital-frontal circumference at the 50th percentile; triangular facies; micrognathia; dental malocclusion; small, tapered teeth; mild thoracolumbar scoliosis; atrophy of interosseous, thenar, and hypothenar hand muscles; atrophy of calf muscles (left greater than right); left club-foot deformity with hammer toes; and right pes cavus with metatarsus adductus. The patient's deep-tendon reflexes were 1 + and symmetric at the triceps, biceps, brachioradialis, and quadriceps, with absent ankle reflexes. Her strength was 4/5 in the distal upper and 3/5 in the distal lower extremities bilaterally, and there were equivocal bilateral Babinski responses. Pain and position sense were reduced in her toes and normal in her legs and arms. NCVs revealed multifocal abnormalities of both median nerves at the wrist and ulnar nerves at the elbow, with no generalized motor slowing in the arms. Atrophy of her distal left leg and both feet limited motor conduction studies, but proximal velocities of her right peroneal nerve were normal with low amplitude, suggesting an axonal-type neuropathy.
Family history revealed carpal tunnel syndrome in the patient's mother (1005), maternal aunt (1187), maternal uncle (1188), and maternal grandfather (1160). The patient's mother was 41-years-old at evaluation. For several years she had had recurrent numbness in her hands and feet, which was sometimes precipitated by stretching, trauma, or overuse. The duration of these symptoms was variable, but they usually persisted for 3-8 weeks and required treatment with physical therapy and splinting. On neurological examination her strength was 4/5 in the ulnar arm and hand muscles, and 5/5 in the lower extremities. Her deep-tendon reflexes were 2+ in the biceps, triceps, and supinators, and 1 + at the quadriceps; trace ankle jerks were present bilaterally. There was normal sensation in the hands and feet, and tenderness over the ulnar nerves at the elbows. NCVs showed abnormalities of the right median motor and bilateral sensory median nerves at the wrists.
The patient's maternal grandfather (1160) was 68-years-old at evaluation. He had had episodic numbness in the hands and feet for >20 years and adult-onset diabetes for 4 years. Significant surgical history included a right ulnar nerve transfer because of nerve compression and numbness, and a removal of a "neuroma" of his foot. On neurological examination he had normal strength in the lower extremities and minimal weakness in the thenar hand muscles. Deep-tendon reflexes were absent in his arms and legs, and sensation to pinprick in the feet was decreased. Other modalities were normal. He had no sensory abnormalities in the hands and his nerves were not enlarged. NCVs revealed a mild sensorimotor polyneuropathy. He also had bilateral median nerve lesions at the wrist and a right ulnar nerve lesion at the elbow.
The patient's maternal aunt (1187) has a diagnosis of carpal tunnel syndrome by NCVs and has had surgery for carpal tunnel syndrome. The patient's maternal uncle (1188) has a diagnosis of carpal tunnel syndrome by NCVs. The patient's sister (1186), at age 7, has not been evaluated for a formal diagnosis of peripheral neuropathy.
Subsequent [molecular] analysis revealed the PMP22 deletion in all affected family members, thus providing an explanation for the carpal tunnel syndrome in this family. The proband 1006 has a more severe and complex clinical phenotype due to the two chromosomal arrangements - an inherited HNPP deletion and a de novo 17p11.2 duplication.
Figure 1 Southern blot analysis revealing the identification of the 7.8-kb HNPP-specific junction fragment in patient 1006 and family members (1160, 1188, 1187, 1005, and 1186) affected with peripheral neuropathy. Lanes 1 and 2 are control YAC clones containing proximal and distal CMT1A-REP, respectively. Lanes 3, 4, and 5 are control genomic DNA from an unaffected individual, a CMT1A duplication patient with the common crossover, and an HNPP patient with the common crossover. Note the 7.8-kb HNPP-specific junction fragment identified by means of a CMTIA-REP probe and not observed in the genomic YACs or in unaffected and CMT1A duplication controls. This HNPP junction fragment cosegregates with carpal tunnel syndrome in this family (lanes 6-15).
Figure 2 A 1.2-Mb junction fragment identified by PFGE. Not1-digested PFGE-separated genomic DNA from family HOU365 was probed with a CLP gene fragment from the SMS-REP. A unique apparent junction fragment (JCT) of ~1.2 Mb was identified in patient 1006. This junction fragment is present in patient 1006 but not in her parents or other family members.
Potocki, L. et al., DNA Rearrangements on Both Homologues of Chromosome 17 in a Mildly Delayed Individual with a Family History of Autosomal Dominant Carpal Tunnel Syndrome. American Journal of Human Genetics 1999; 64:471-478.
Summary and graphics reprinted from AMERICAN JOURNAL OF HUMAN GENETICS published by the University of Chicago Press, copyright © 1999 by the American Society of Human Genetics. All rights reserved.
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