Hereditary sensory neuropathy with spastic paraplegia

European Journal of Paediatric Neurology (2004) 8, 95–99

www.elsevier.com/locate/ejpn

CASE STUDY

Hereditary sensory neuropathy with spastic paraplegia Louisa Kherbaoui-Redouania, Dominique Plotonb, Michel Abelya, Nathalie Bednareka, Audrey Stourbea, Pascal Sabourauda, Jacques Mottea,* a

´ de neurope ´diatrie, Service de pe ´diatrie A, American Memorial Hospital, Department of Pediatrics, Unite C.H.U., 47 rue Cognacq Jay, 51092 Reims cedex, France b Department of Molecular Biology and Pathology, University Hospital of Reims, Reims cedex, France Received 21 August 2003; received in revised form 18 November 2003; accepted 8 December 2003

KEYWORDS Hereditary sensory neuropathy; Spastic paraplegia; Histamine test

Summary We report the case of a 4-year-old boy with hereditary sensory neuropathy manifesting as insensitivity to pain in all four limbs and associated with spastic paraplegia. The patient was referred with multiple injuries to his fingers suggestive of self-mutilation and attributed to psychiatric disturbance. Clinical examination corrected the diagnosis by revealing insensitivity to pain in all four limbs, associated with spastic paraplegia. The histamine test reaction was positive, nerve biopsy and electrophysiological investigations confirmed sensory nerve involvement and the diagnosis of hereditary sensory neuropathy. Classification and treatment of such rare diseases is difficult and a multidisciplinary approach is often necessary. Q 2004 European Journal of Paediatric Neurology. Published by Elsevier Ltd. All rights reserved.

Introduction Hereditary sensory neuropathies are rare and still pose considerable problems both for classification and treatment. There are five types, and the genetic element in these diseases has yet to be clarified. Gene defects have been reported for type I with a missense mutation in the SPTLC1 gene which maps to chromosome 9q22.1 Indo et al.2 proposed the human TRKA homolog (NTRK1) as a candidate of the mutation in congenital insensitivity to pain with anhidrosis syndrome (CIPA) or hereditary *Corresponding author. Tel.: þ 33-326-78-78-99; fax: þ 33326-78-82-62.

sensory neuropathy type IV and V.3 A gene (IKBKAP) is also identified in the type III or Riley – Day syndrome 4,5 mapped in the chromosome 9. Several reported cases have been difficult to classify in that the clinical presentations can be very different. In particular, one report indicates that type IV and V are allelics.6 The child we present here posed such a problem.

Case study The 4-year-old boy was initially referred at 2 years 6 months for chronic injuries to his fingers. He was

1090-3798/$ - see front matter Q 2004 European Journal of Paediatric Neurology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2003.12.006

96

L. Kherbaoui-Redouani et al.

Figure 1 Multiple trauma to fingers and multiple scarring of the hands.

the only child of healthy unrelated parents with no history of neurological disease. He was born normally after an uneventful pregnancy. The injuries were caused by repeated biting of his fingers, beginning at the age of 1 year and attributed to psychological disturbance related to his parents’ divorce. He had previously been seen on several occasions for severe mutilating injuries, sometimes requiring surgical treatment. There was obvious deformity of the fingers, with trophic abnormalities and scarring from several injuries (Fig. 1). The child communicated easily and his intellectual development was normal. He was just learning to walk with a walking frame device. He crawled and could stand with support. He had spastic paraplegia with hypertonia of the adductor muscles and pes equinus. He presented mild contractures of the hips, knees and ankles. The patellar reflexes were brisk and multikinetic, the

ankle jerks were absent and biceps tendon reflexes were present. He did not present amyotrophy or muscle weakness. There was severely defective sensation to heat and pain, which did not appear to involve the proximal part of the limbs, the trunk, or the head. Pinprick sensation was impaired distally in all four limbs and temperature sensation lost in the hands, feet and lower legs. It was not possible to determine if joint position and vibration sense were impaired. But we noted that when we presented a ‘sweet’ in his hand, he did not sense it. Tear production was normal. There was no history of tongue biting, nor of unexplained febrile episodes or abnormal sweating. Nor was there any associated neuro-vegetative disorder. Examination of the tongue was normal. Ophthalmologic examination showed no impairment of the pupils, nerve optic or retina. Hearing tests were not performed but language development was normal. Radiography of the bone structure of the hands revealed deformity and demineralization of the phalanges. Cerebral and spinal cord MRI were normal. Uricemia, hemogram and blood ionogram were normal. Intradermal injection of histamine (0.5 ml 1/1000 solution) caused a papule and erythema of about 10 cm in diameter. Nerve conduction studies clearly showed a dissociation between motor and sensory nerve conduction. Motor nerve conduction was normal in the lower limbs (Table 1). Sensory studies showed absence of ulnar and median sensory nerve action potentials. It was impossible to identify sensory evoked potentials for the upper and the lower limbs. This suggests the impairment of the somesthesia fibers.

Table 1 Electrophysiology. Motor nerve conduction Nerve and site Median L Wrist Elbow Ulnar L Wrist Elbow Median R Wrist Elbow Ulnar R Wrist Elbow

Latency (ms)

Amplitude (mV)

Segment

Latency (ms)

Distance (mm)

Conduction (m/s)

2.2 5.8

9.127 7.357

Wrist–elbow Elbow–axillary

3.6 1

125 85

33 69

2.2 4.7

6.356 5.531

Wrist–elbow Elbow–axillary

2.5 2

127 125

49 52

2.5 5.7

3.458 3.010

Wrist–elbow Elbow–axillary

3.2 1.7

160 50

48 28

1.9 4.8

6.003 8.685

Wrist–elbow Elbow–axillary

2.9 2.4

157 100

52 40

ms, millisecond; mV, mill volt; mm, millimeters; m/s, meter/second.

Hereditary sensory neuropathy with spastic paraplegia

97

Figure 2 Electronmicroscopy study of sural nerve biopsy, with extreme rarefaction of myelinated fibers (single line and arrow) and with normal quantities of non-myelinated fibers (dotted line and double arrows).

A biopsy sample from the sural nerve was fixed in 2% glutaraldehyde solution and then in 2% osmic acid. After dehydration the sample was embedded in Epikotte 812. After polymerisation at 60 8C ultra thin sections were stained with uranium acetate and lead citrate. Observation with a Hitachi electron microscope evidenced that normal quantities of non-myelinated fibers were present in the cross-section of the nerve (Fig. 2). However, very rare myelinated fibers were observed (single line and arrow).

Discussion Insensitivity to pain is a symptom which can be found in various congenital and hereditary conditions. Forms of insensitivity to pain can be found in hereditary sensory neuropathy (HSN) with the so called generalized lack of awareness of pain (Table 2). Among the sensory neuropathies there are various clinical entities, which are very difficult to classify. The easiest classification is Dyck’s classification,7 but there are forms which cannot

Table 2 Hereditary sensory neuropathies. Classified forms Dyck’s classification HSN type I

Acronyms and references Denny–Brown hereditary sensory neuropathy or Thevenard ulcero-mutilating acropathy, Nicholson et al.16 Hereditary sensory and autonomic neuropathy, Bockers’s et al.17 Riley–Day syndrome, Blumenfield et al.5 Congenital insensibility to pain with anhidrosis, Indo et al.2 Hereditary sensory and autonomic neuropathy, Houlden6

HSN type II HSN type III HSN type IV HSN type V Non-classified forms HSN with bone dysplasia Progressive pan-neuropathy with hypotonia Congenital autonomic dysfunction with insensitivity to pain HSN with ataxia HSN with spastic paraplegia

generalized

Others forms Related forms: indifference to pain

References Axelrod18 Croall19 Axelrod20 Robinson21 Thomas11 Cavanagh14

98

L. Kherbaoui-Redouani et al.

Table 3 Review of published cases of hereditary sensory neuropathy with spastic paraplegia. Cases

Age at onset

Mode of onset

Reflexes

Intelligence

1 Thomas 2 Thomas 3 Thomas 4 Thomas 5 Thomas 6 Cavanagh 7 Cavanagh 8 Cavanagh 9 Cavanagh 10 Cavanagh Our case

10 years 10 years 11 years 17 years 2 years 2 years 14 months 2 years 3 years

Ulceration of fingers Ulceration of toes Ulceration of toes Ulceration of toes Spastic paraplegia Spastic paraplegia Spastic paraplegia Spastic paraplegia and mutilation Spastic paraplegia Spastic paraplegia Biting of fingers

? Brisk in lower limbs Brisk in lower limbs Brisk Reduced in lower limbs Reduced Brisk in lower limbs ? ?

? ? Normal Normal Normal Low average IQ ? ? ?

Brisk and polykinetic

Normal

1 year

be classified. The case we report might correspond to Dyck’s classification HSN type II on the basis of the clinical and electrophysiological evidence and particularly on the sural nerve biopsy.8 However, the coexistence of spastic paraplegia raised questions regarding this classification. In addition, the histamine test reaction was clearly positive in our case, whereas it is usually negative in HSN type II. However, Ogden9 reported a case with clinical symptoms and nerve biopsy compatible with the diagnosis of HSN type II but also with a positive histamine reaction. This demonstrates the difficulty of classification with symptoms which might correspond to two types.10 Among the non-classified types there is a form of hereditary sensory neuropathy associated with spastic paraplegia. Table 3 summarizes the main characteristics of the published cases. Thomas has reported five cases in three separate families.11 Onset in four of these cases was relatively late, i.e. in young adulthood or adolescence, with progressive evolution. In addition, the condition usually affects the lower limbs in the form of chronic ulcers, whereas in our case onset occurred early in infancy and mainly involved the upper limbs. The fifth case reported by Thomas occurred earlier, revealed by pyramidal syndrome at 4 years of age requiring tenotomy of both Achilles tendons.11 In these five cases the symptoms were progressive, both in terms of loss of sensation and in the spastic paraplegia. Onset occurred very early in our patient and it was difficult to classify the sensory disorders in view of his youth and inability to provide information. For the same reasons it has been difficult to evaluate outcome, although over time he has presented with fewer severe mutilations because he no longer bites his fingers. Nerve biopsy and electronmicroscopy demonstrated rarefaction of myelinated fibers, as in all five cases reported by Thomas. It is notable that in the early onset case he reported, which was also the most severe, there was significant myelinated fiber

Other symptoms

Sphincter disorders Frequent mutilation Renal amylosis

deficiency, whatever the caliber, as in our case. This suggests that this considerable deficiency in myelinated fibers might be correlated with severity of disease, although histopathology studies failed to demonstrate signs of active degeneration. Several hypotheses can be proposed concerning the genetic element in this clinical entity. Van Epps and Kerr12 reported 26 cases, later considered by Khalifeh and Zellweger in 1963 to be of autosomal dominant transmission.13 Reporting five cases in 1979, Cavanagh14 suggested autosomal recessive transmission or a de novo dominant mutation, as also suggested by Thomas for two families including two brothers and two sisters, respectively, with healthy but consanguinous parents. The fifth case corresponded to a de novo mutation. No gene has to date been identified.

Conclusion This case demonstrates the difficulties encountered in classifying this type of disorder, which only complicates the already difficult treatment, especially for the chronic damage caused by insensitivity to pain which is often the first sign.15 It is often necessary for treatment to be multidisciplinary, including dermatologists, neurologists, surgeons, orthopedic surgeons and psychologists.

References 1. Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 2001;27:309—12. 2. Indo Y, Tsuruta M, Hayashida Y, et al. Mutations in the TRKA/ NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 1996;13:485—8. 3. Mardy S, Miura Y, Endo F, et al. Congenital insensitivity to pain with anhidrosis: novel mutation in the TRKA(NTRK1)

Hereditary sensory neuropathy with spastic paraplegia

4.

5.

6.

7.

8.

9.

10.

11.

gene encoding a high-affinity receptor for nerve growth factor. Am J Hum Genet 1999;64:1570—9. Anderson SL, Coli R, Daly IW, et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet 2001;68:753—8. Blumeneld A, Slaugenhaupt SA, Axelrod FB, et al. Localization of the gene for familial dysautonomia on chromosome 9 and definition of DANN markers for genetic diagnosis. Nat Genet 1993;4:160—4. Houlden H, King RH, Hashemi-Nejad A, et al. A novel TRKA (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. Ann Neurol 2001;49: 521—5. Dyck PJ, Mellinger JF, Reagan TJ, et al. Not ‘indifference to pain’ but varieties of hereditary sensory and autonomic neuropathy. Brain 1983;106:373. Nukada H, Pollock M, Haas F. The clinical spectrum and morphology of type II hereditary sensory neuropathy. Brain 1982;105:647—65. Ogden TE, Robert F, Carmichael EA. Some sensory syndromes in children: indifference to pain and sensory neuropathy. J Neurol Neurosurg Psychiat 1959;22:267—76. Person JR, Rogers RS, Rhodes KH. Congenital sensory neuropathy, report of an atypical case. Arch Dermatol 1977;113:954—7. Thomas PK, Misra VP, King RHM, et al. Autosomal hereditary sensory neuropathy with spastic paraplegia. Brain 1994;117: 651—9.

99

12. Van Epps C, Kerr HD. Familial lumbosacral syringomyelia. Radiology 1940;35:160—73. 13. Khalifeh RR, Zellweger H. Hereditary sensory neuropathy with spinal cord disease. Neurology 1963;13:405—11. 14. Cavanagh NP, Eames RA, Galvin RJ, Brett EM, Kelly RE. Hereditary sensory neuropathy with spastic paraplegia. Brain 1979;102:79—94. 15. Redouani L, Le ´aute ´-Labreze C, Ramirez de Villar S, Taı¨eb A, Sarlangue J. Difficulte ´s de prise en charge d’une insensibilite ´ a ` la douleur. Arch Pediatr 2002;7:701—4. 16. Nicholson GA, Dawkins JL, Blair IP, Auer-Grumbach M, Brahmblatt SB, Hulme DJ. Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe. Am J Hum Genet 2001; 69:655—9. 17. Bocker M, Benes P, Bork K. Persistent skin ulcers, mutilations, and acro-osteolysis in hereditary sensory and autonomic neuropathy with phospholipid excretion: report of a family. J Am Acad Derm 1989;21:736—9. 18. Axelrod FB, Pearson J, Tapperberg J, et al. Congenital sensory neuropathy with skeletal dysplasia. J Pediatr 1982; 102:727—30. 19. Croall GB, Bates SR, Iannaccone ST, et al. Paucifascicular congenital sensory neuropathy in identical twins. Am J Dis Child 1986;140:589—95. 20. Axelrod FB, Cash R, Pearson J. Congenital autonomic dysfunction with universal painloss. J Pediatr 1983;1:60—4. 21. Robinson GC, Jan JE, Miller JR. A new variety of hereditary sensory neuropathy. Hum Genet 1977;35:153—61.