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Skeletal fluorosis causing high cervical myelopathy
Journal of Clinical Neuroscience 16 (2009) 828–830
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case Reports
Skeletal fluorosis causing high cervical myelopathy Hrishikesh Kumar a, Marina Boban b,*, Mona Tiwari c a b c
Department of Neurology, S.K. Soni Hospital, Jaipur, Rajasthan, India Department of Neurology, Zagreb School of Medicine and University Hospital Centre, Budmanijeva 3, HR–10000 Zagreb, Croatia Getwell Polyclinic and Hospital, Jaipur, Rajasthan, India
a r t i c l e
i n f o
Article history: Received 15 May 2008 Accepted 21 August 2008
Keywords: Fluorosis Cervical cord compression Ossification Ligamentum flavum Quadriplegia
a b s t r a c t Skeletal fluorosis is endemic in some parts of the world and is the result of life-long ingestion of high amounts of fluoride in drinking water. Its clinical presentation is characterized mostly by bone and dental changes with later ossification of many ligaments and interosseous membranes. We present a rare case of high cervical myelopathy caused by ossification of the posterior longitudinal ligament and ligamentum flavum in a patient from an area endemic for skeletal fluorosis. The clinical presentation of skeletal fluorosis and treatment options are discussed. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction Skeletal fluorosis is endemic in some parts of the world due to life-long ingestion of high amounts of fluoride in drinking water. It is characterized by dental changes and diffuse densification of bones with ossification of many ligaments and interosseous membranes. Neurological complications occur in 10% of patients, mostly in late stages of the disease.1 We present a rare case of high cervical myelopathy caused by ossification of the posterior longitudinal ligament and ligamentum flavum in a patient from an area endemic for skeletal fluorosis.
2. Case report A 48-year-old male from a semi-urban area of Rajasthan, India, presented in March 2005 to the Department of Neurology of Soni Hospital, a tertiary care hospital in Jaipur, with stiffness and weakness of upper and lower limbs. His symptoms started insidiously in 2003 with slowly progressive stiffness of the neck and back. At the end of 2004 he started having difficulty in walking and a few months later he developed symmetrical weakness of both hands with urinary incontinence. He denied any traumatic injury of the cervical spine. His past medical history was unremarkable. On examination, severe spastic quadriparesis with spastisticy as the dominant finding was revealed accompanied by signs of posterior column involvement and generally brisk deep tendon reflexes with clonus. In addition, diffuse opaque white areas with brownish mottling and discrete pitting were observed on his teeth. A urodynamic study revealed an overactive urinary bladder. At the time of presentation, he * Corresponding author. Tel.: +385 91 539 5594; fax. +385 1 238 8045. E-mail address: [email protected] (M. Boban).
was not on any regular medication. His brother had similar problems with neck and back stiffness, without other neurological complaints. Plain X-rays of cervical (Fig. 1a) and thoracic spine revealed markedly increased bone density and ossification of the ligamentum flavum. Additionally, ossification of the patellar tendons and interosseous membranes of the ribs were found. A CT scan revealed ossification of the ligamentum flavum and posterior longitudinal ligament at several cervical and thoracic levels. On axial scans ossification of the ligamentum flavum was shown as bilateral hyperdensities separated from the lamina by a discrete gap (Fig. 1b). MRI revealed dorsal and ventral ridging with flattening of the spinal cord due to ossification of the ligamentum flavum and posterior longitudinal ligament at the cervical and thoracic levels C1– T1, more marked at levels C2–4 with intramedullary gliotic changes (Fig. 2). Similar changes were observed at level T11–12. Urine fluoride level was 11.2 mg/L (normal range, 0.2–1.1 mg/L) with unremarkable renal function. The fluoride level in drinking water was 4.5 mg/L (permitted level, <1.5 mg/L). Somatosensory evoked potentials showed slowing of posterior column conduction for all limbs. The first procedure, decompressive laminectomy at T11–12 was performed in May 2005 followed by median corpectomy at C2–3 with a bone graft fusion 1 month later. Both resulted in slight recovery of neurological deficits. At the last neurological examination, in November 2007, the patient was unable to stand without support, was severely spastic and incapacitated by frequent flexor spasms and required intermittent catheterization. 3. Discussion The diagnostic criteria for fluorosis include life-long habitation in an endemic region, regular consumption of water with fluoride
Case Reports / Journal of Clinical Neuroscience 16 (2009) 828–830
829
Fig. 1. Cervical anteroposterior view radiograph (a) showing diffuse marble-white appearance of the cervical vertebral bodies due to markedly increased bone density as well as calcification of the ligamentum flavum (spaces between the vertebral arches). Axial CT scan (b) revealing ossification of the posterior longitudinal ligament (arrowhead) and bilateral hyperdensities due to ossification of the ligamentum flavum separated from the lamina by a narrow gap (arrows).
Fig. 2. Sagittal T2-weighted MRI scan showing dorsal and ventral ridging with flattening of the spinal cord at cervical and thoracic levels C1–T1, more marked at C2–4 with intramedullary gliotic changes (arrow).
levels above 1.2 ppm, urine fluoride levels above 1.5 mg/L and typical dental changes. Furthermore, diffuse densification of bones and ossification of bony insertions of many ligaments, discs and interosseous membranes are seen on X-rays.2,3 Skeletal fluorosis also occurs in non-endemic areas, mostly caused by inhalation of
dust and fumes containing fluoride emitted by manufacturing processes4 or renal function impairment.1 There are also rare cases caused by habitual consumption of large volumes of extra-strength instant tea.5 Our patient met the diagnostic criteria for skeletal fluorosis.2 He lives in a region endemic for skeletal fluorosis with fluoride concentrations in drinking water of up to 24 mg/L, despite a safe limit of 1.5 mg/L (World Health Organization standards6 and Bureau of Indian Standards7). He also had high urine fluoride levels as well as the typical dental and skeletal changes found in skeletal fluorosis. Ossification of the ligamentum flavum caused by skeletal fluorosis is rare. There are only a few case reports and one small case series describing this condition, mostly located in the thoracic region.8 Although neurological complications may occur in 10% of cases with skeletal fluorosis, mostly in the later stages of disease,1 myelopathy due to ossification of the posterior longitudinal ligament and/or ligamentum flavum in patients with skeletal fluorosis has been uncommonly reported and mostly localized in the lower thoracic part of the spinal cord.8,9 To the best of our knowledge, the association of high cervical myelopathy and skeletal fluorosis has not been reported. Decompressive laminectomy is recommended in selected cases of myelopathy caused by ossification of the ligamentum flavum and/or posterior longitudinal ligament. Interestingly, the surgical procedure for ossified ligamentum flavum caused by fluorosis is much easier and safer than that due to other etiologies due to sparing of the dura mater (therefore, postoperative cerebrospinal fluid leak is reduced).10 However, postsurgical long-term outcome is poor in patients with skeletal fluorosis, mostly due to the nature of the underlying disease. Additionally, poor outcome is also related to length of symptoms, with a longer duration predicting a worse outcome.11 Both the long duration of symptoms as well as further postsurgical high fluoride intake in drinking water resulted in poor neurological outcome in our patient. In conclusion, in patients with compressive myelopathy secondary to ossification of the ligamentum flavum and/or posterior longitudinal ligament, fluorosis should be considered, especially in endemic regions, as well as for patients with impaired renal function or habitual consumption of high-fluoride beverages.
830
Case Reports / Journal of Clinical Neuroscience 16 (2009) 830–831
References 1. Reddy DR. Fluorosis. In: Ramamurthi B, Tandon PN, editors. Textbook of Neurosurgery. New Delhi: Churchill Livingstone; 1996. p. 798–803. 2. Yildiz M, Akdogan M, Tamer N, et al. Bone mineral density of the spine and femur in early postmenopausal Turkish women with endemic skeletal fluorosis. Calcif Tissue Int 2003;72:689–93. 3. Wang Y, Yin Y, Gilula LA, et al. Endemic fluorosis of the skeleton: Radiographic features in 127 patients. AJR Am J Roentgenol 1994;162:93–8. 4. Bhavsar BS, Desai VK, Mehta NR. Neighborhood fluorosis in Western India. Fluoride 1985;18:80–92. 5. Whyte MP, Totty WG, Lim VT, et al. Skeletal fluorosis from instant tea. J Bone Miner Res 2008;23:759–69. 6. Gorchev HG, Ozolins G. WHO guidelines for drinking-water quality. WHO Chron 1984;38:104–8.
7. Bureau of Indian Standards. BIS: 10500, ‘‘Indian Standard Code for Drinking Water”, BIS, India. 1983. 8. Wang W, Kong L, Zhao H, et al. Thoracic ossification of ligamentum flavum caused by skeletal fluorosis. Eur Spine J 2007;16:1119–28. 9. Gupta RK, Agarwal P, Kumar S, et al. Compressive myelopathy in fluorosis: MRI. Neuroradiology 1996;38:338–42. 10. Muthukumar N. Ossification of the ligamentum flavum as a result of fluorosis causing myelopathy: report of two cases. Neurosurgery 2005;56: E622. 11. Ben Hamouda K, Jemel H, Haounet S, et al. Thoracic myelopathy caused by ossification of the ligamentum flavum: a report of 18 cases. J Neurosurg 2003;99:157–61.
doi:10.1016/j.jocn.2008.08.028
The neurofilament light chain gene (NEFL) mutation Pro22Ser can be associated with mixed axonal and demyelinating neuropathy Satyakam Bhagavati *, Paul J. Maccabee, Weimin Xu Department of Neurology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
a r t i c l e
i n f o
Article history: Received 15 April 2008 Accepted 21 August 2008
Keywords: Neurofilament Mutation Neuropathy Charcot-Marie-Tooth disease
a b s t r a c t We report the detailed clinical, electrophysiological and molecular analysis of a patient with CharcotMarie-Tooth (CMT) disease. DNA sequencing of the coding sequences of the neurofilament light chain polypeptide (NEFL) gene revealed a c.64C > T heterozygous, missense mutation resulting in a Pro22Ser amino acid substitution. Clinical and electrophysiological studies revealed a mixed axonal and demyelinating neuropathy, with widespread demyelination involving both proximal and distal nerve segments. Mutations at this site in the NEFL gene have been previously linked to an axonal neuropathy or distal nerve demyelination. Our results emphasize the complexity of genotype–phenotype correlations in CMT and underline the possible importance of host factors and gene interactions in the development of clinical phenotypes. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction The most common inherited peripheral neuropathies are Charcot-Marie-Tooth disease Type 1 (CMT1) and Type 2 (CMT2). 1CMT1 is characterized by segmental demyelination and slow nerve conduction velocities (median nerve conduction velocity < 38 m/s). In CMT2 there is axonal loss and regenerative sprouting with normal or slightly reduced conduction velocities.2 CMT is genetically heterogenous and mutations in 36 genes have been described.3 Mutations in the neurofilament light chain polypeptide gene (NEFL) have been described in 2% of CMT cases.4 To date 13 different NEFL mutations have been described in 66 CMT patients.5 We describe here the detailed clinical and electrophysiological features of a patient with a c.64C > T (Pro22Ser) mutation of the NEFL gene. 2. Case Report An 18-year-old Caucasian man presented with a history of difficulty with running and poor ‘‘balance” since the age of 5 years. His mother noted foot deformities when he was six years of age. On examination there was bilateral wasting of the intrinsic mus-
* Corresponding author. Tel.: +1 718 270 2841; fax: +1 718 270 3840. E-mail address: [email protected] (S. Bhagavati).
cles of the hands and calves, with pes cavus and hammer toes. Mild (4/5) distal weakness was present in both upper and lower limbs. Sharp perception and vibration was decreased circumferentially bilaterally and symmetrically in hands and feet. All deep tendon reflexes were absent. There was no palpable nerve hypertrophy, scoliosis, limb ataxia, hearing impairment, postural hypotension or respiratory involvement. His mother and three siblings (2 sisters and 1 brother) had no neurological abnormality. The father was unavailable for testing. Mutations in the common CMT-causing genes (PMP22, MPZ, and Cx32) were excluded by commercial testing (Athena Diagnostics, Worcester, MA, USA). The four exons of the NEFL gene from the patient were amplified by polymerase chain reactions (PCR) using previously reported primers.4 By sequencing PCR fragments we identified a heterozygous missense mutation in the first exon of the NEFL gene, c.64 C > T (Fig. 1) resulting in a Pro22Ser amino acid substitution in the patient, but not in any of the family members. Since the father was not available for testing it was not possible to determine whether the mutation was sporadic or inherited. Nerve conduction studies (Table 1) were suggestive of mixed demyelinating and axonal neuropathy. Demyelination was suggested by prolonged terminal latencies and moderately slow motor conduction velocities (range, 25–33 m/s) and prolonged F wave responses, in the demyelinating range.6 No conduction block was noted. Associated axonal involvement was shown by very low amplitude motor-evoked responses and the presence of active
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case Reports
Skeletal fluorosis causing high cervical myelopathy Hrishikesh Kumar a, Marina Boban b,*, Mona Tiwari c a b c
Department of Neurology, S.K. Soni Hospital, Jaipur, Rajasthan, India Department of Neurology, Zagreb School of Medicine and University Hospital Centre, Budmanijeva 3, HR–10000 Zagreb, Croatia Getwell Polyclinic and Hospital, Jaipur, Rajasthan, India
a r t i c l e
i n f o
Article history: Received 15 May 2008 Accepted 21 August 2008
Keywords: Fluorosis Cervical cord compression Ossification Ligamentum flavum Quadriplegia
a b s t r a c t Skeletal fluorosis is endemic in some parts of the world and is the result of life-long ingestion of high amounts of fluoride in drinking water. Its clinical presentation is characterized mostly by bone and dental changes with later ossification of many ligaments and interosseous membranes. We present a rare case of high cervical myelopathy caused by ossification of the posterior longitudinal ligament and ligamentum flavum in a patient from an area endemic for skeletal fluorosis. The clinical presentation of skeletal fluorosis and treatment options are discussed. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction Skeletal fluorosis is endemic in some parts of the world due to life-long ingestion of high amounts of fluoride in drinking water. It is characterized by dental changes and diffuse densification of bones with ossification of many ligaments and interosseous membranes. Neurological complications occur in 10% of patients, mostly in late stages of the disease.1 We present a rare case of high cervical myelopathy caused by ossification of the posterior longitudinal ligament and ligamentum flavum in a patient from an area endemic for skeletal fluorosis.
2. Case report A 48-year-old male from a semi-urban area of Rajasthan, India, presented in March 2005 to the Department of Neurology of Soni Hospital, a tertiary care hospital in Jaipur, with stiffness and weakness of upper and lower limbs. His symptoms started insidiously in 2003 with slowly progressive stiffness of the neck and back. At the end of 2004 he started having difficulty in walking and a few months later he developed symmetrical weakness of both hands with urinary incontinence. He denied any traumatic injury of the cervical spine. His past medical history was unremarkable. On examination, severe spastic quadriparesis with spastisticy as the dominant finding was revealed accompanied by signs of posterior column involvement and generally brisk deep tendon reflexes with clonus. In addition, diffuse opaque white areas with brownish mottling and discrete pitting were observed on his teeth. A urodynamic study revealed an overactive urinary bladder. At the time of presentation, he * Corresponding author. Tel.: +385 91 539 5594; fax. +385 1 238 8045. E-mail address: [email protected] (M. Boban).
was not on any regular medication. His brother had similar problems with neck and back stiffness, without other neurological complaints. Plain X-rays of cervical (Fig. 1a) and thoracic spine revealed markedly increased bone density and ossification of the ligamentum flavum. Additionally, ossification of the patellar tendons and interosseous membranes of the ribs were found. A CT scan revealed ossification of the ligamentum flavum and posterior longitudinal ligament at several cervical and thoracic levels. On axial scans ossification of the ligamentum flavum was shown as bilateral hyperdensities separated from the lamina by a discrete gap (Fig. 1b). MRI revealed dorsal and ventral ridging with flattening of the spinal cord due to ossification of the ligamentum flavum and posterior longitudinal ligament at the cervical and thoracic levels C1– T1, more marked at levels C2–4 with intramedullary gliotic changes (Fig. 2). Similar changes were observed at level T11–12. Urine fluoride level was 11.2 mg/L (normal range, 0.2–1.1 mg/L) with unremarkable renal function. The fluoride level in drinking water was 4.5 mg/L (permitted level, <1.5 mg/L). Somatosensory evoked potentials showed slowing of posterior column conduction for all limbs. The first procedure, decompressive laminectomy at T11–12 was performed in May 2005 followed by median corpectomy at C2–3 with a bone graft fusion 1 month later. Both resulted in slight recovery of neurological deficits. At the last neurological examination, in November 2007, the patient was unable to stand without support, was severely spastic and incapacitated by frequent flexor spasms and required intermittent catheterization. 3. Discussion The diagnostic criteria for fluorosis include life-long habitation in an endemic region, regular consumption of water with fluoride
Case Reports / Journal of Clinical Neuroscience 16 (2009) 828–830
829
Fig. 1. Cervical anteroposterior view radiograph (a) showing diffuse marble-white appearance of the cervical vertebral bodies due to markedly increased bone density as well as calcification of the ligamentum flavum (spaces between the vertebral arches). Axial CT scan (b) revealing ossification of the posterior longitudinal ligament (arrowhead) and bilateral hyperdensities due to ossification of the ligamentum flavum separated from the lamina by a narrow gap (arrows).
Fig. 2. Sagittal T2-weighted MRI scan showing dorsal and ventral ridging with flattening of the spinal cord at cervical and thoracic levels C1–T1, more marked at C2–4 with intramedullary gliotic changes (arrow).
levels above 1.2 ppm, urine fluoride levels above 1.5 mg/L and typical dental changes. Furthermore, diffuse densification of bones and ossification of bony insertions of many ligaments, discs and interosseous membranes are seen on X-rays.2,3 Skeletal fluorosis also occurs in non-endemic areas, mostly caused by inhalation of
dust and fumes containing fluoride emitted by manufacturing processes4 or renal function impairment.1 There are also rare cases caused by habitual consumption of large volumes of extra-strength instant tea.5 Our patient met the diagnostic criteria for skeletal fluorosis.2 He lives in a region endemic for skeletal fluorosis with fluoride concentrations in drinking water of up to 24 mg/L, despite a safe limit of 1.5 mg/L (World Health Organization standards6 and Bureau of Indian Standards7). He also had high urine fluoride levels as well as the typical dental and skeletal changes found in skeletal fluorosis. Ossification of the ligamentum flavum caused by skeletal fluorosis is rare. There are only a few case reports and one small case series describing this condition, mostly located in the thoracic region.8 Although neurological complications may occur in 10% of cases with skeletal fluorosis, mostly in the later stages of disease,1 myelopathy due to ossification of the posterior longitudinal ligament and/or ligamentum flavum in patients with skeletal fluorosis has been uncommonly reported and mostly localized in the lower thoracic part of the spinal cord.8,9 To the best of our knowledge, the association of high cervical myelopathy and skeletal fluorosis has not been reported. Decompressive laminectomy is recommended in selected cases of myelopathy caused by ossification of the ligamentum flavum and/or posterior longitudinal ligament. Interestingly, the surgical procedure for ossified ligamentum flavum caused by fluorosis is much easier and safer than that due to other etiologies due to sparing of the dura mater (therefore, postoperative cerebrospinal fluid leak is reduced).10 However, postsurgical long-term outcome is poor in patients with skeletal fluorosis, mostly due to the nature of the underlying disease. Additionally, poor outcome is also related to length of symptoms, with a longer duration predicting a worse outcome.11 Both the long duration of symptoms as well as further postsurgical high fluoride intake in drinking water resulted in poor neurological outcome in our patient. In conclusion, in patients with compressive myelopathy secondary to ossification of the ligamentum flavum and/or posterior longitudinal ligament, fluorosis should be considered, especially in endemic regions, as well as for patients with impaired renal function or habitual consumption of high-fluoride beverages.
830
Case Reports / Journal of Clinical Neuroscience 16 (2009) 830–831
References 1. Reddy DR. Fluorosis. In: Ramamurthi B, Tandon PN, editors. Textbook of Neurosurgery. New Delhi: Churchill Livingstone; 1996. p. 798–803. 2. Yildiz M, Akdogan M, Tamer N, et al. Bone mineral density of the spine and femur in early postmenopausal Turkish women with endemic skeletal fluorosis. Calcif Tissue Int 2003;72:689–93. 3. Wang Y, Yin Y, Gilula LA, et al. Endemic fluorosis of the skeleton: Radiographic features in 127 patients. AJR Am J Roentgenol 1994;162:93–8. 4. Bhavsar BS, Desai VK, Mehta NR. Neighborhood fluorosis in Western India. Fluoride 1985;18:80–92. 5. Whyte MP, Totty WG, Lim VT, et al. Skeletal fluorosis from instant tea. J Bone Miner Res 2008;23:759–69. 6. Gorchev HG, Ozolins G. WHO guidelines for drinking-water quality. WHO Chron 1984;38:104–8.
7. Bureau of Indian Standards. BIS: 10500, ‘‘Indian Standard Code for Drinking Water”, BIS, India. 1983. 8. Wang W, Kong L, Zhao H, et al. Thoracic ossification of ligamentum flavum caused by skeletal fluorosis. Eur Spine J 2007;16:1119–28. 9. Gupta RK, Agarwal P, Kumar S, et al. Compressive myelopathy in fluorosis: MRI. Neuroradiology 1996;38:338–42. 10. Muthukumar N. Ossification of the ligamentum flavum as a result of fluorosis causing myelopathy: report of two cases. Neurosurgery 2005;56: E622. 11. Ben Hamouda K, Jemel H, Haounet S, et al. Thoracic myelopathy caused by ossification of the ligamentum flavum: a report of 18 cases. J Neurosurg 2003;99:157–61.
doi:10.1016/j.jocn.2008.08.028
The neurofilament light chain gene (NEFL) mutation Pro22Ser can be associated with mixed axonal and demyelinating neuropathy Satyakam Bhagavati *, Paul J. Maccabee, Weimin Xu Department of Neurology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
a r t i c l e
i n f o
Article history: Received 15 April 2008 Accepted 21 August 2008
Keywords: Neurofilament Mutation Neuropathy Charcot-Marie-Tooth disease
a b s t r a c t We report the detailed clinical, electrophysiological and molecular analysis of a patient with CharcotMarie-Tooth (CMT) disease. DNA sequencing of the coding sequences of the neurofilament light chain polypeptide (NEFL) gene revealed a c.64C > T heterozygous, missense mutation resulting in a Pro22Ser amino acid substitution. Clinical and electrophysiological studies revealed a mixed axonal and demyelinating neuropathy, with widespread demyelination involving both proximal and distal nerve segments. Mutations at this site in the NEFL gene have been previously linked to an axonal neuropathy or distal nerve demyelination. Our results emphasize the complexity of genotype–phenotype correlations in CMT and underline the possible importance of host factors and gene interactions in the development of clinical phenotypes. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction The most common inherited peripheral neuropathies are Charcot-Marie-Tooth disease Type 1 (CMT1) and Type 2 (CMT2). 1CMT1 is characterized by segmental demyelination and slow nerve conduction velocities (median nerve conduction velocity < 38 m/s). In CMT2 there is axonal loss and regenerative sprouting with normal or slightly reduced conduction velocities.2 CMT is genetically heterogenous and mutations in 36 genes have been described.3 Mutations in the neurofilament light chain polypeptide gene (NEFL) have been described in 2% of CMT cases.4 To date 13 different NEFL mutations have been described in 66 CMT patients.5 We describe here the detailed clinical and electrophysiological features of a patient with a c.64C > T (Pro22Ser) mutation of the NEFL gene. 2. Case Report An 18-year-old Caucasian man presented with a history of difficulty with running and poor ‘‘balance” since the age of 5 years. His mother noted foot deformities when he was six years of age. On examination there was bilateral wasting of the intrinsic mus-
* Corresponding author. Tel.: +1 718 270 2841; fax: +1 718 270 3840. E-mail address: [email protected] (S. Bhagavati).
cles of the hands and calves, with pes cavus and hammer toes. Mild (4/5) distal weakness was present in both upper and lower limbs. Sharp perception and vibration was decreased circumferentially bilaterally and symmetrically in hands and feet. All deep tendon reflexes were absent. There was no palpable nerve hypertrophy, scoliosis, limb ataxia, hearing impairment, postural hypotension or respiratory involvement. His mother and three siblings (2 sisters and 1 brother) had no neurological abnormality. The father was unavailable for testing. Mutations in the common CMT-causing genes (PMP22, MPZ, and Cx32) were excluded by commercial testing (Athena Diagnostics, Worcester, MA, USA). The four exons of the NEFL gene from the patient were amplified by polymerase chain reactions (PCR) using previously reported primers.4 By sequencing PCR fragments we identified a heterozygous missense mutation in the first exon of the NEFL gene, c.64 C > T (Fig. 1) resulting in a Pro22Ser amino acid substitution in the patient, but not in any of the family members. Since the father was not available for testing it was not possible to determine whether the mutation was sporadic or inherited. Nerve conduction studies (Table 1) were suggestive of mixed demyelinating and axonal neuropathy. Demyelination was suggested by prolonged terminal latencies and moderately slow motor conduction velocities (range, 25–33 m/s) and prolonged F wave responses, in the demyelinating range.6 No conduction block was noted. Associated axonal involvement was shown by very low amplitude motor-evoked responses and the presence of active