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Charcot-Marie-Tooth disease type 1A (CMT1A) is the most frequent form of CMT (also known as hereditary motor and sensory neuropathy, HMSN). The inheritance is autosomal dominant and is usually associated with a duplication at chromosome 17p11.2. This region contains the gene of the peripheral myelin protein 22 (PMP22) and an increased concentration of PMP22 seems to be responsible for neurological phenotype in patients with 17p11.2 duplication.1 Therefore, a gene dosage effect is the most likely pathogenetic mechanism for CMT1A.
Partial trisomy 17p is an unusual chromosomal disorder rarely reported in Europe, the clinical features of which have not been definitely established.2-6 Growth retardation, craniofacial anomalies, and developmental delay seem to constitute a characteristic phenotype associated with this condition.6 Moreover, the identification of patients with 17p trisomy with a uniform demyelinating neuropathy similar to that seen in patients with CMT1A, has provided further in vivo evidence supporting the gene dosage hypothesis.7-9 In this report, we describe an additional case of a child with de novo partial duplication of 17p associated with CMT1A.
A 7 year old boy was born at 41 weeks of gestation by spontaneous vaginal delivery after artificial amniorrexis. There was prenatal history of oligohydramnios. His parents were healthy and non-consanguineous and the family history for neurological or genetic diseases was negative. At the time of birth, the apgar score was 7 because he had meconium aspiration syndrome. Physical examination showed low weight (2.755 kg, percentile 3), normal length (49.5 cm, percentile 25) and microcephaly (33 cm, percentile 3). Facial dysmorphic characters included hypertelorism, downslanted palpebral fissures, migrognathia, plane philtrum, and prominent ears. At the age of 3 months, there was a continued growth failure (weight 4.100 kg, percentile 3; length 56.5 cm, percentile 3) and a right microphthalmia and divergent strabismus were noted. At 8 months of age, there was a marked global developmental delay. At that time, cerebral echography, brain auditory evoked potentials, and MRI were within normal limits. Subsequently, the patient was sent to a centre for mentally retarded children where he has been taking intensive schooling including psychomotor and speech therapies.
In June 1999, the patient was referred to our hospital for electrophysiological evaluation to test the possibility of impairment of the peripheral nervous system. At that time, the patient had no weakness, gait disturbances, or sensory complaints but the diagnosis of partial duplicaton of 17p was the reason for testing. Neurological examination showed facial dysmorphic characters (as mentioned above), remarkable hyperactivity, pronounced expressive speech delay, generalised hyporeflexia, pes cavus, and incipient tibioperoneal atrophy. Gower's sign was negative. Enlarged nerves were not found. There was no sensory deficit, but detailed testing could not be performed. Electrophysiological studies were done with a MEDELEC Shappire 4 electromyographer. The EMG showed a mixed pattern and polyphasic motor unit potentials. No fibrillation potentials or positive sharp waves were found. Motor nerve conduction velocities were obtained on the patient and his mother. The patient's motor conduction velocities were uniformly slowed in the limbs and F waves were markedly delayed (table 1).
Sensory nerve conduction measurements were not done because of the child's anxiety . These findings were consistent with the presence of a demyelinating neuropathy in keeping with the diagnosis of CMT1. By contrast, his mother's median and ulnar motor nerve conduction velocities were normal (53.7 m/s and 70 m/s, respectively).
Chromosome analysis of the patient showed the presence of extra chromosomal material in 17p. Fluorescence in situ hybridisation confirmed the diagnosis of partial duplication of the short arm of chromosome 17 and demonstrated that extra material was located in the region beyond band 17p13.3. The mother's and father's karyotypes were normal. Therefore, these findings were compatible with a de novo interstitial duplication of 17p. Duplication analysis was done using microsatellite markers (D17S921 and DS17S955) from within the region of chromosome 17p11.2, known to be duplicated in CMT1A and containing the PMP22 gene. Gene dosage experiments with these microsatellite markers demonstrated that the patient was a carrier of a chromosome 17 with 17p11.2 duplication, which is often associated with the CMT1A phenotype. His parents were heterozygous for these markers but signals of equal intensity were found for both alleles.
Most of the clinical features described here are similar to those previously detailed in several children with de novo partial duplications of 17p.2-6 All of them had low birthweight, growth retardation, developmental delay, and craniofacial dysmorphic characters such as hypertelorism, downslanted palpebral fissures, smooth philtrum, and abnormal ears. In addition, our patient had divergent strabismus, microphthalmia, pronounced hyperactivity, and remarkable speech delay. To date, only a few cases of this rare chromosomal condition have been published and clinical data are scarce. However, our finding supports the hypothesis that partial trisomy 17p has a typical phenotype.5 6 Recently, some authors have also shown abnormal nerve conduction velocities in patients with this disorder.7-9 Therefore, we carried out an electrophysiological study to examine the status of the peripheral nerves, detecting the existence of a demyelinating neuropathy in keeping with the diagnosis of CMT1. It is important to emphasise that clinical manifestations such as weakness, gait disturbances, and sensory deficits were absent in the child. This fact strongly supports the need for electrophysiological evaluation in all patients with trisomy 17p even when the anomalies denoting the existence of peripheral nervous system impairment are absent.
Lupski et al 1 studied a patient with 17p partial trisomy with decreased nerve conduction velocities whose molecular analysis showed the CMT1A duplication. On the basis of their findings, the authors hypothesised that the CMT1A phenotype resulted from a gene dosage effect. Later Chance et al 7 ratified the association of trisomy 17p and CMT1A and provided further evidence supporting a gene dosage mechanism. Since then, only a few cases have been published.8 9 One of these studies examined the presence of PMP22 gene duplication in four patients with partial trisomy.8 Two of these patients showed slowing of conduction velocities and exhibited PMP22 gene duplication. By contrast, in two patients with normal conduction velocities the PMP22 gene was not duplicated. This investigation demonstrated that the presence of demyelinating neuropathy is directly associated with PMP22 gene duplication and corroborated the gene dosage model.
In summary, we describe another case of a patient with 17p trisomy whose electrophysiological evaluation showed the existence of a demyelinating neuropathy type CMT1. Our finding contributes support to the idea that trisomy 17p is responsible for a typical phenotype and that nerve conduction studies should be included in the routine examinations in all patients with this chromosomal disorder. In addition, our patient adds more in vivo evidence supporting a gene dosage effect in CMT1A.
We are grateful to Dr Orera for the initial cytogenetic evaluation and Dr O Combarros for his kind contribution to the bibliographic review.
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