Hereditary neuropathies with self-mutilation - IOS Press

Journal of Pediatric Neurology 2004; 2(4): 205-211 www.jpneurology.org

ORIGINAL ARTICLE

Hereditary neuropathies with self-mutilation Natan Gadoth 1, Eliyah Mass 2 1

Department of Neurology, Meir General Hospital, Kfar Saba, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2 Department of Pediatric Dentistry, Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel

Abstract Although self-mutilation (SM) is not rare in the general population, the most common causes for this mode of destructive behavior are mental retardation and psychiatric ailments. There are 2 types of neuropathies with mutilation, those with spontaneous mutilation of tissues and the others in which the patients mutilate themselves. A number of hereditary disorders are associated with SM. Among the eight MIM (Mendelian Inheritance in Man) entries associated with SM, there are four conditions, which are associated with peripheral neuropathy (choreoacanthocytosis,.acanthocytosis with neurological impairment, congenital insensitivity to pain with anhydrosis and the paroxysmal neuropathy of type I tyrosinemia). The other four (Tourette syndrome, Lesch-Nyhan syndrome, LeschNyhan phenotype with normal hypoxanthine guanine phosphoribosyle transferase and Cridu-chat syndrome) are not associated with peripheral neuropathy. It is quite surprising that in the latest editions of the classical textbooks of pediatrics, pediatric neurology and adult neurology SM is mentioned only with regard to Lesch-Nyhan syndrome. In this paper, we describe our experience with a number of hereditary mutilating neuropathies and review some of the recent advances in the neurobiology of SM. The recognition and awareness of this outstanding clinical sign may be helpful in reaching a correct diagnosis and offering

Correspondence: Natan Gadoth M.D., Department of Neurology, Meir General Hospital, Kfar Saba, 44281 Israel. Tel: 972-9-7472828, fax: 972-9-7471317. E-mail: [email protected] Received: April 01, 2004. Revised: May 20, 2004. Accepted: May 22, 2004.

symptomatic treatment, to avoid potential tissue damage at an earlier stage of the disease. (J Pediatr Neurol 2004; 2(4): 205-211). Key words: hereditary neuropathy, self-mutilation, familial dysautonomia.

Introduction Self-mutilation (SM) or self-injurious behavior is an act directed towards one’s self, which results in tissue damage (1). About 5-17% of people with intellectual and developmental disabilities, 4% of the general population and 21% of persons with psychiatric disorders suffer from SM (2,3). The occurrence of SM among non-retarded patients with neurological impairment is quite rare and the knowledge, understanding and awareness of this aberrant behavior by general practitioners and neurologists alike seem to be quite restricted. In a survey conducted by us among medical students in their senior years and residents in medicine and pediatrics, they were asked about known conditions, which are associated with SM. The only condition they could come-up with was LeschNyhan syndrome (LNS). This limited knowledge might reflect the fact that LNS is the only condition associated with self-injurious behavior mentioned in the recent editions of Menkes “Child Neurology”, Nelson’s “Pediatrics” and “Principles of Neurology” by Adams and Victor, all well-known and popular textbooks used by students and residents in pediatrics and neurology (4-6). Self-mutilation is quite common in Tourette syndrome (GTS) (7), and may also be seen in choreo-acanthocytosis (8), and in a number of clinical syndromes with associated profound mental retardation such as Prader-Willi, Smith-Magenis, de-Lange and Fragile-X syndrome. Interestingly, in type 1 tyrosinemia, SM was observed only during bouts of peripheral neuropathy in the context of a transient “neurological crisis”. In-between the crises, affected infants were observed to function normally (9). In the 5p deletion syndrome, better

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known by the eponym Cri-du-chat, which is associated with early mental retardation, Van Buggenhout et al. (10) have recently reported on the appearance of periods of destructive behavior and SM, which started between the ages of 16-47 years. Although the results of detailed neurological examination and nerve conduction studies were not reported by the authors, the possibility exists that transient peripheral neuropathy, similar to that observed in type 1 tyrosinemia, may be the cause of SM in these patients. There are only two reports on congenital global sensory loss and SM. Barry et al. (11) described two unrelated children with global sensory loss and Axlerod et al. (12) reported some years later three unrelated non-Jewish children, who had in addition, “dysautonomic“ features which closely resembled those seen in children with familial dysautonomia. SM was rarely seen in patients with acquired neuropathy or spinal cord injury. Roach et al. (13) have described two such patients. One child mutilated the fingers distal to a traumatic median nerve injury, while the other injured himself during the course of neuropathy due to insecticide poisoning (13). Interestingly, Swoboda et al. (14) have reported on a familial form of carpal tunnel syndrome manifested in a infant with SM of the digits innervated by the entrapped median nerve. Among 127 consecutive patients with obstetric brachial plexus injury, 4.7% were noted to mutilate the affected limb (15). Self-mutilation in spinal cord injury was observed in four children and was attributed to dysesthesias in the paralyzed mutilated limbs (16). Although severe sensory loss, as seen in almost all the hereditary sensory neuropathies, may, at least theoretically, cause sensory deprivation and associated SM, there are fortunately only a few hereditary neuropathies associated with selfinjurious behavior. The recognition of those may be of diagnostic and therapeutic value, which justify “splitting” these entities rather than “clumping” them into the bulk of “hereditary sensory neuropathies”. Hereditary neuropathies with body mutilation The most common hereditary neuropathies are the hereditary motor and sensory neuropathies (HMSN) types I and II. Although the commonest are autosomal dominant, there are rare families with autosomal recessive HMSN II and some without linkage to HMSN II, or hereditary sensory neuropathy I loci. In the members of those families, mutilation but not self-mutilation, was the result of severe distal sensory loss leading to non-healing accidental injuries, recurrent osteomyelitis and osteonecrosis, spontaneous amputations and bony

disfiguration (17,18). Clinically, those conditions may be regarded as mutilating neuropathies, in contrast to neuropathies with SM. The assumption that SM by patients with neuropathy is due to sensory deprivation should be challenged, as many patients with severe sensory impairment will never mutilate themselves, while others with a relatively mild impairment will do so. Although SM is believed to provide a rapid temporary relief from feelings of depersonalization, guilt, rejection, hallucinations, sexual preoccupation, and chaotic thoughts, it is difficult to accept such an explanation for animal models with SM, such as the experimental “mutilating foot” rat model with an autosomal recessive transmitted mutation in the mf gene (19), the autosomal recessive “toe necrosis”, shorthaired pointer pup model (20) and the English pointer dog model (21). Interestingly, the common neuropathological denominator for these three conditions is loss of myelinated and unmyelinated fibers, mainly in the dorsal roots and peripheral nerves with severe loss of dorsal root ganglion cells. During the last 25 years we have diagnosed and followed a number of children and adolescents affected with two forms of hereditary sensory and autonomic neuropathy (HSAN), i.e. Familial dysautonomia and congenital insensitivity to pain with anhydrosis (CIPA), both relatively common in Israel. These conditions are known to be associated with profound SM, especially affecting the oro-dental structures and share the loss of small myelinated and unmyelinated axons in the peripheral nerves. Hereditary sensory and autonomic neuropathy type III-familial dysautonomia Familial dysautonomia (FD) seems to be the appropriate name for this multisystem disorder where autonomic and sensory neuropathy is present, but can not account for all its peculiar clinical features. An autosomal recessive transmitted, tissue-specific expression of a splicing mutation in the IKBKAP gene was recently shown to cause FD (22). Although rare worldwide, it is quite common among Jews of Ashkenazi origin (Ashkenazim who have settled in Europe-Russia, Poland and part of Europe which was included in the “AustroHungarian” empire since the 14th century). Frequent intermarriage within this orthodox population resulted in several “Ashkenazi” Jewish diseases such as infantile Tay-Sachs disease (TSD), Gaucher disease and torsion dystonia. It has recently been shown that the majority of families with FD used to live in Poland and the carrier rate in this particular population is significantly higher (1:18) than that calculated for all the families affected (1:30) (23).


motor conduction velocities are within the normal range but the sensory evoked potentials show a progressive decrease in amplitude with time, compatible with progressive axonal loss.

Figure 1. Eight-year-old boy with familial dysautonomia. Dislocation and avulsion of maxillary incisors due to selfmutilation.

FD is characterized by severe hypotonia, areflexia, and inability to suck and swallow at birth (24). A characteristic and unique finding is an almost complete lack of tongue fungiform papillae (25). Additional common features are failure to thrive, labile blood pressure, cyclic vomiting, recurrent aspiration pneumonia, orthostatic hypotension, bouts of unexplained fever, skin blotching, excessive sweating and lack of tearing. Their presence is highly suggestive of the diagnosis in an Ashkenazi Jewish infant (26). The neuropathological data on classical FD are quite scanty consisting of a dismal number of published autopsied cases, mainly due to the fact that permission for autopsy is not readily granted according to Jewish tradition. This may also explain in part why nonconsistent central nervous system structural abnormalities have been reported. In the peripheral nervous system there is a prominent neuronal loss in the dorsal root ganglia together with hypoplasia of the dorsal root entry zone and the Lissauer tract. The autonomic and especially the parasympathetic ganglia are hypoplastic (27). Substance P immunoreactivity is reduced in the substantia gelatinosa (28). The neuropathology of the peripheral nerves is better documented since sural nerve biopsies are more available. There is a disproportional progressive loss of small myelinated and especially unmyelinated fibers with no evidence of active fiber degeneration. Schwann cell clusters are decreased in number compared to other forms of neuropathy (29,30). The reported results of nerve conduction velocities in FD patients are inconsistent. Moreover, in many publications reporting clinical cases, conduction velocities were not mentioned. In two previous reports motor conduction velocity was found to be somewhat decreased and the amplitude of the sensory evoked potentials in the ulnar nerve was markedly reduced (29,31). In our experience,

Self-mutilation in familial dysautonomia Since 1980 we have been providing free dental care to a relatively large group of children and adolescents with FD. Many patients had signs of unexplained oro-dental trauma due to SM (Figure 1). This observation was quite unique as at that time the literature related to oro-dental SM in FD was limited to a single case report (32). We found evidence of SM in 22 children under our care and concluded that the oral cavity is a common site for SM (33). In a further report on 38 patients with FD (34) we have found that 14 (36.8%) patients showed significant oro-dental SM in the form of tongue biting (9), self extraction of teeth (6), lip biting (2) and cheek and nostril self injury-each in a single patient. In several patients, a number of sites were observed as targets for SM. A few patients mutilated the tip of the fingers and the nails, resulting in traumatic amputations of the distal phalanx (Figures 2a and 2b). The patients with SM were not different from those without SM in regard to severity of autonomic dysfunction, emotional status and cognition. Hereditary sensory and autonomic neuropathy type IV (CIPA) This condition is caused by mutations of the TRKA/NGF gene located at 1q21-q22 (35). This gene encodes the receptor tyrosine kinase for nerve growth factor (NGF) and mice lacking the TRKA gene do not react to pain although sweating is preserved (36). The association between CIPA and the TRKA/NGF system suggests that this system plays a major role in development and function of pain perception and thermo-regulatory sweating. Seventeen different mutations of the TRKA/NGF gene have been reported in families with CIPA. In one out of 10 unrelated Israeli-Bedouin families with CIPA, no mutation of the TRKA/NGF gene was found suggesting that other genes could be associated with CIPA (37). The classical clinical features are bouts of unexplained fever during early infancy, leading to recurrent hospital admissions during which an extensive and frequently a negative search for infection is carried out. This may go on until it is noticed that the fever is related to environmental temperature and that the infant fails to cry when intramuscular injections are given. Parents or caregivers may notice the lack of perspiration on hot and humid days. Self-mutilation may be noticed as early as 6 months of age when the teeth start to erupt. The affected infant is observed sucking

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A

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Figures 2a and 2b. Plucked finger nails of an 11-year-old boy (a) and an 8-year-old girl (b) with familial dysautonomia.

Figure 3. Oral cavity of a 4-year-old girl with CIPA with missing primary incisors and maxillary canines and scarred tongue due to self-mutilation. Note the extensive abrasion of the maxillary first primary molars.

forcefully and biting repeatedly the rigid surface of toys (Figure 3). Somewhat later, the self injurious behavior takes the form of severe mutilation of fingertips and tongue, self-extraction of nails and self inflicted amputation of fingers and toes. Restlessness, temper tantrums, breath-holding spells, insomnia and almost no social communication are the early manifestations of moderate to severe mental retardation. The characteristic clinical features, in addition to SM, consist of almost global lack of sweating and total lack of pain perception. In spite of these outstanding abnormalities the neurological examination is usually normal, including deep tendon and superficial skin reflexes. Skeletal X-ray survey will frequently disclose old fractures. The cerebrospinal fluid, brain imaging, needle electromyography and motor conduction velocities are normal, while sensory evoked responses are of low amplitude, indicating axonal neuropathy, which is also the explanation for the

lack of a flare after intradermal histamine injection. The typical neuropathological findings in the peripheral nerve (sural nerve biopsy), consist of normal density of packed myelinated nerve fibers with almost total lack of unmyelinated fibers, or Schwann cells without any axons (Figures 4a and 4b). The skin electronmicroscopy shows normal appearing sweat glands, which lack terminal unmyelinated axons (38,39). Although one may attribute SM to significant mental retardation present in children with CIPA, some of our patients, with CIPA and severe SM, were not profoundly retarded. In children with marked distal anesthesia, foot deformities with missing toes, chronic anesthetic foot ulcers and recurrent local osteomyelitis of the metatarsal bones, it should be obvious that this is not the result of SM. One should consider the diagnosis of mutilating neuropathy of the HMSN II, especially if there are other family members similarly affected (Figure 5). Pathophysiology of self-mutilation A neurobiological basis for SM has been developed during the last few years supported by data collected from patients and animal models of LNS. It was shown with positron emission tomography that decreased dopamine transporters and decreased DOPA-decarboxylase activity is present in putamen and caudate of patients indicating a reduction in dopaminergic neuronal arborization. The reduction of dopamine transporters was proportionate to the reduction in the activity of hypoxanthine-guaninephosphoribosyle-transferase in variant forms of LNS. However, reduction of dopamine transporters was similar in patients with severe dystonia and SM and those without SM (40,41). This observation suggested that neurotransmitters other than dopamine might be involved in the mechanism of


A

B

Figures 4a and 4b. Electromicrographs of sural nerve biopsy obtained from a 6-year-old girl with CIPA. (a) Total lack of unmyelinated fibers (1x5000), (b) Normal appearing myelin sheath (1x9100).

dopaminergic mediation of SM. Treatment of self-mutilation

Figure 5. The spontaneously mutilated limbs of a 16 years old boy with autosomal recessive mutilating neuropathy (HMSN II).

SM. Recently, a link between impaired dopaminergic activity and SM was established in mice. It was previously shown in primates and rodents that systemic administration of high doses of dopamine release stimulants including amphetamine, methamphetamine and pemoline, was followed by self-biting and self-injurious behavior (42-44). The systemic administration of the low doses of the L-type calcium channel agonist ± Bay K 8644 to juvenile mice results in reduced motor activity, while high doses caused dystonia, stiffness, twisting and repetitive self-biting progressing to SM (45). Kasim and Jinnah (46) have recently shown that when animals were pretreated with dopamine depleting agents such as reserpine and tetrabenazine, there was a marked reduction of SM induced by ± Bay K 8644. This elegant experiment confirms the

There is no information on treatment of SM due to neurological disorders. We have tried several methods of treatment in our patients with FD and CIPA. Grinding the sharp edges of the primary mandibular incisors in a 10-month-old girl with FD who had a Riga-Fede traumatic ulcerative granuloma on the base of the tongue resulted in healing within a few days of the procedure (34). Casting the fingers as a radical way to prevent selfamputation has failed, since the children chewed on the casts and succeeded in reaching their fingers. Successful treatment by placing acrylic devices on the teeth was observed in a 19 months old patient (32). However, this procedure may be hazardous, because of the risk of aspiration of the device especially in FD. Drugs commonly used to reduce pain and tingling in peripheral neuropathies such as amitriptyline, carbamazepine and phenytoin were ineffective. In an experimental model of acquired neuropathy with SM in the rat, administration of guanethidine decreased the threshold for sensory stimuli in the denervated limb but failed to alter SM (47). References 1. 2.

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