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Hereditary sensory and autonomic neuropathy with ataxia and late onset
Clinical Neurology and Neurosurger! Clinical
Neurology
and Neurosurgery
96 (1994) 191-196
Case report
Hereditary sensory and autonomic neuropathy Adriana Marbin?*,
with ataxia and late onset
Giovanni Paves?, Giovanna Cenacchib, Anna Mazzucchi”, Paola Predab, Franc0 Gemignani” “Institute of Neurology, University of‘ Parma,via de1 Quartierc, 4. I-43100 Parma. Italy. ‘Institute of Electron Microscopy, University of Bologna, Bologna, Italv Received
21 September
1993; revised
6 December
1993; accepted
13 December
1993
Abstract
We report two brothers affected by a dominantly inherited form of hereditary sensory and autonomic neuropathy (HSAN), characterized by clinical features of sensory ataxia, and by late onset in the 6th decade. Sural nerve biopsy in the proband showed almost complete loss of myelinated fibers, and relative sparing of unmyelinated fibers. This family showed an atypical presentation of HSAN, which is usually characterized by acrodystrophic manifestations of infantile or juvenile onset. Although a few reports of HSAN presenting with late onset and/or ataxia appeared, this is the first report of a family with dominant HSAN characterized by late onset sensory ataxia. Key words:
Hereditary sensory neuropathy;
Ataxia; Nerve biopsy
1. Introduction The classification of hereditary sensory and autonomic neuropathies (HSAN) is based on a combination of the clinical and genetic features [1,2]. We report a family with HSAN of dominant type characterized by late onset sensory ataxia, which represents a further clinical variant.
2. Case reports Case 1 A 66-year-old man complained of unsteady gait, with a tendency to widen the stepping base at the age of 60 years. Unsteadiness was worse in the dark. In the last 2 years he reported that he had often to hold on to something in order to stand erect, as if he had ‘stepped into a hole’. For about 1 year he had been feeling a tingling sensation in his legs, especially during the night. He also reported frequent dizziness when getting up in the morn-
*Corresponding
author.
Fax: (0521) 282776.
0303-8467/94/$7.00 0 1994 Elsevier SSDI 0303-8467(93)EOl 15-8
Science B.V. All rights
reserved
ing, slow digestion, tendency to constipation, slow start in urinating, and reduced foot perspiration. Neurological examination showed normal cranial nerve function, apart from deafness, and normal limb muscle bulk and strength. There was moderate dysmetria in the finger-to-nose and heel-to-knee tests when visual control was suppressed. Deep tendon reflexes were absent in the ankles. Light touch sensation was mildly reduced in the feet. Vibration sense was moderately reduced in the lower limbs, especially in the knees. Position sense was markedly impaired in the extremities. Tcmperature sensation was diffusely impaired throughout the body. Disturbance of pain sensation was distributed in a similar pattern, and the stimuli were perceived with delay and with an unpleasant quality. Standing was maintained with widened stepping base, and was impossible without visual control. Gait was wide-based, with inability to tandem walk. Extensive laboratory investigations gave normal results except for a slight increase in serum IgA (393 mg/ 100 ml; normal 116-374). Audiometric study showed sensorineural hearing loss. Chest x-ray, EEG, CSF examination, CT scan and MRI of the brain, and myelogram were normal. Autonomic function tests provided
2
3
4
6
5
I
9
q
affected
normal
00
a
by history
III@
to
probably affccttd
11
12
13
14
15
16
(deceased)
normal by examination
Fig. 1. Family tree, showing autosomal dominant inheritance.
abnormal values: orthostatic hypotension 30 mm Hg (normal, I 10); handgrip test 0 mm Hg (normal, 2 16 mm Hg); Valsalva ratio 1.08 (normal, 2 1.2 1); deep breathing test 2.5 beats/min (normal, 215); lying-to-standing test 1.00 (normal, ~1.04) (methods and normal values according to Ewing and Clarke [3]). Neurophysiological study showed normal EMG findings in the distal muscles of the limbs. Examination of the sensory nerves showed extremely reduced or absent Table 1 Nerve conduction studies Case 1 Motor nerves _ Peroneal amplitude (2 3 mV) distal latency (I 5.5 ms) conduction velocity (2 43 m/s) Median amplitude (->6 mV) distal latency (< 4.5 ms) conduction velocity (2 49 m/s) Sensory nerves - Sural amplitude (> 6 ,A’) conduction velocity (> 46 m/s) - Median amplitude (2 4.5 pV) conduction velocity (2 48 m/s) Ulnar amplitude (2 4 PV) conduction velocity (> 47 m/s)
Case 2
R
L
R
L
11 3.8 44.2
7.5 3.6 42.6
7.5 3.1 47
7 2.9 46.7
10 4.3 46.9*
NR* -
0.5* 35.9*
NR* -
1.2* 28.7*
1* 40.3*
2.5* 30.8*
R = right; L = left; NR = no response; * = abnormal.
l* 43.4%
sensory action potentials (SAP) and reduced conduction velocities (CV), whereas there were only minor alterations in the motor nerves (Table 1). Median and peroneal somatosensory evoked potentials were normal. A sympathetic skin response of low-normal amplitude (0.2 mV) was elicited in the lower limbs. Case 2 The patient’s brother, 62-year-old, also reported unbalance in the last few years. Neurologic examination revealed marked sensory ataxia, absent Achilles tendon reflexes, and deficit in all sensation modalities in the lower limbs. EMG of the limb muscles was normal. Electrophysiological findings were normal for the motor nerves, with extremely reduced amplitude or absence of the SAP and slowed CV of sensory nerves (Table 1). Sympathetic skin response was of borderline amplitude (0.1 mV). Family study (Fig. I) Unbalance with onset around the 6th decade was reported also in the father and in another brother, both deceased. The patients’ sons, aged 18 to 40, were examined but no symptoms or signs of neuromuscular disorders were detected. Electrophysiological study and autonomic function tests were performed in the 3S-year-old daughter of patient 2, with negative results. Neuropathological study A combined biopsy of the sural nerve 5 cm above the lateral malleolus and of the peroneus brevis muscle was
A. Marbini et al. IClinical
Fig. 2. Sural nerve biopsy:
semithin
section
Neurology
showing
and Neurosurgery
96 (1994)
severe and diffuse myelinated
193
191-196
fiber loss (toluidine
blue stain. x400)
perfor med in the case 1, and examined with standard methc Fds for histology, histochemistry, and electron microscc ‘PY [41.
The sural nerve consisted of 11 fascicles with an increased total fascicular area of 1.673 mm2 (nom nal, 8.4k 1.6 fascicles, and transverse fascicular area of
Fig. 3. Sural nerve biopsy: semithin
fibers with excessively
section showing
a few surviving
myelinated
thin myelin sheaths (toluidine
blue stain. xl 000).
Fig. 4. Sural nerve biopsy: unmyelinated (electron microscopy, Xl I 000)
fibers with myelinoid
bodies (arrows)
0.842 f 0.218 mm2, according to Nukada et al. [5]). Semithin sections and morphometric study showed extremely severe loss of myelinated fibers of all diameters (622/ mm2) (Fig. 2) with slight difference in proportion between small (47%) and large fibers (53%). Occasional surviving fibers showed thin myelin sheaths, active axonal degeneration, and regeneration (Fig. 3). Unmyelinated fiber population seemed to be relatively less involved (7772/mm2; control 32 000/mm2), however, aspects of axon damage (Fig. 4) and frequent stacks of flattened Schwann cell processes and collagen pockets suggesting previous fiber degeneration (Fig. 5) were present. Search for amyloid was negative. Only 13 teased fibers, which showed normal features, could be isolated due to severe myelinated fiber loss. Muscle biopsy iindings were normal.
3. Discussion A diagnosis of HSAN was established in this family, despite atypical features, as we could rule out a few other inherited diseases which may produce similar clinical manifestations. Familial amyloid polyneuropathy type 1
into the axoplasm.
Endoneurial
collagen
fibrils are densely packed
is also characterized by sensory loss and autonomic dysfunction; however, pain and temperature sensation, rather than proprioception, is selectively involved, and ocular abnormalities are usually prominent [6]. Amyloid was not present in the nerve biopsy of our proband. In multiple system atrophy, autonomic dysfunction is associated with clinical and neuroradiological evidence of extrapyramidal or cerebellar involvement, not seen in our patients, whereas peripheral nerve involvement, if present, is usually subclinical [7]. HSAN has been classified by Dyck [I], mainly based on mode of inheritance, into HSAN type I (dominant autosomal), HSAN type II (recessive), HSAN type III (familial dysautonomia), HSAN type IV (diffuse absence of pain sensation with anhidrosis), HSAN type V (absence of pain sensation and anhidrosis with selective loss of small fibers). In addition, a family with X-4inked recessive HSAN has been reported [8]. As clinical manifestations are not homogeneous within the genetic categories of HSAN, further subgroups of HSAN have been proposed on clinical grounds [2]. The family reported here, however, does not fit into current classifications of HSAN, as it was characterized by exceptionally late onset (not before the 6th decade), and by sensory ataxia.
A. Marbini et al. IClinical Neurology and Neurosurgery 96 (1994)
Fig. 5. Sural nerve biopsy:
numerous
multilamellar
stacks
(arrows)
instead of the acrodystrophic manifestations which are usually seen in HSAN. Despite these atypical symptoms, this form could be classified as HSAN type I because of the hereditary transmission of likely dominant type. The other varieties of HSAN could be excluded as they are congenital and usually show a significant reduction of the fascicular area [5]. Predominantly ataxic manifestations have been described in rare cases of dominant [9] and recessive [lo] or sporadic [5,11] HSAN; in the two brothers described by Staal and Mechelse [lo] there was a late onset in the 5th to 6th decade. Previous cases of dominant and sporadic HSAN showed association with deafness [9,12,13,14] and increased serum IgA level [15,16]. Acrodystrophic symptoms are not constant in HSAN I [l], and in our patients the persistence of a certain amount of unmyelinated nociceptive fibers may have contributed to their prevention. Even though onset of HSAN I is usually in the 2nd to 3rd decade and no families with onset as late as in our case have been described, there is however great variability in the onset and progression of the disease [l]. Our morphometric findings of profound loss of myelinated fibers with relative preservation of unmyelinated fibers did not coincide with previous data
and collagen
pockets
195
191-196
(arrowheads)
(electron
microscopy,
x40 800).
in HSAN I by Dyck [l] (loss of unmyelinated fibers and small myelinated fibers) and by Danon and Carpenter [ 171(uniform loss for every fiber type), rather resembling the pathologic features of HSAN II [5,18]. In view of the limited number of cases described in the literature, a precise clinical and morphological characterization of HSAN is still problematic. This report emphasizes the occurrence of HSAN with unusual features of sensory ataxia of late onset, a clinical variant not considered in current classifications [1,2]. Although the present family exhibited a likely dominant inheritance, a similar clinical pattern seems to occur also in recessive [lo] and sporadic [5,11] HSAN. In addition, it should be noted that this form is phenotypically identical to the pattern of late onset sensory ataxia of the so-called chronic idiopathic ataxic neuropathy [19,20], in which, however, a genetic basis has not been advanced.
References [I] Dyck, nantly Dyck,
P.J. (1984) Neuronal atrophy and degeneration predomiaffecting peripheral sensory and autonomic neurons. In: P.J., Thomas, P.K.. Lambert. E.H. and Bunge R. (Eds),
196
il. Marbini
ef al. I c’limcul
Neurologv
Peripheral Neuropathy, vol. 2, W.B. Saunders, Philadelphia, PA, pp. 1551-1599. [2] Donaghy, M., Hakin, R.N., Bamford, J.M., Garner, A., Kirkby, G.R., Noble, B.A., Tazir-Melboucy, M., King, R.H.M. and Thomas, P.K. (1987) Hereditary sensory neuropathy with neurotrophic keratitis. Description of an autosomal recessive disorder with a selective reduction of small myelinated nerve fibres and a discussion of the classification of the hereditary sensory neuropathies. Brain, 110: 563-583. [3] Ewing, D.J. and Clarke, B.F. (1982) Diagnosis and management of diabetic autonomic neuropathy. Br. Med. J., 285: 916-918. [4] Gemignani, F., Guidetti, D., Bizzi, P., Preda, P., Cenacchi, G. and Marbini, A. (1992) Peroneal muscular atrophy with hereditary spastic paraparesis (HMSN V) is pathologically heterogeneous. Acta Neuropathol., 83: 196201. [5] Nukada, K., Pollock, M. and Haas, L.F. (1982) The clinical spectrum and morphology of type II hereditary sensory neuropathy. Brain, 105: 647-665. [6] Hersch, MI. and McLeod, J.G. (1987) Peripheral neuropathy associated with amyloidosis. In: Vinken, P.J., Bruyn, G.W., Klawans, H.L. and Matthews, W.B. (Eds.), Handbook of Clinical Neurology, vol. 5 1, Neuropathies, Elsevier Science Publishers B.V., Amsterdam, pp. 413428. [7] Bannister, R. (1988) Clinical features of autonomic failure. A. Symptoms, signs, and special investigations. In: Bannister, R. (Ed.), Autonomic Failure, Oxford University Press, Oxford. pp. 267-281. [8] Jestico, J.V., Urry, P.A. and Efphimiou, J. (1985) An hereditary sensory and autonomic neuropathy transmitted as an X-linked recessive trait. J. Neurol. Neurosurg. Psychiat., 48: 1259-1264. [9] Robinson, G.C., Jan, J.E. and Miller, R.J. (1977) A new variety of hereditary sensory neuropathy. Hum. Genet., 35: 153-161.
und Neurosurger.v
Yt, (1994)
IYI-
100
[IO] Staal, A. and Mechelse, K. (1978) Hereditary sensory neuropathy. a new type. Hum. Genet.. 42: I15- 118. [I l] Serlenga, L., Trizio, M., Pozio, G. and Di Pietro, F. (1987) Hereditary sensory and autonomic neuropathy presenting as ataxia. Acta Neurol., 42: 12-18. [12] Hicks, E.P. (1922) Hereditary perforating ulcer of the foot. Lancer i: 319-321. [13] Horoupian, D.S. (1989) Hereditary sensory neuropathy with deafness: a familial multisystem atrophy. Neurology, 39: 244248. [14] Hageman, G., Hilhorst, B.G.J. and Rozeboom, A.R. (1992) Is there involvement of the central nervous system in hereditary sensory radicular neuropathy? Clin. Neurol. Neurosurg., 94: 49954. [15] Whitaker, J.N., Falchuck, Z.M., Engel, W.K., Blaese, R.M. and Strober, W. (1974) Hereditary sensory neuropathy: association with increased synthesis of immunoglobulin. Arch. Neurol.. 30: 359-371. [ 161 Iwabuchi, S., Yoshino, Y. and Goto, H. (1976) Analysis of serum immunoglobulin in hereditary sensory radicular neuropathy. J. Neurol. Sci., 30: 29-32. [17] Danon, M.J. and Carpenter, S. (1985) Hereditary sensory neuropathy: biopsy study of an autosomal dominant variety. Neurology, 35: 12261229. [18] Ohta, M., Ellefson, R.D., Lambert, E.H. and Dyck, P.J. (1973) Hereditary sensory neuropathy, type II: clinical, electrophysiological, histologic, and biochemical studies of a Quebec kinship. Arch. Neurol., 29: 23-37. [19] Dalakas, M. (1986) Chronic idiopathic ataxic neuropathy. Ann. Neurol., 19: 545-554. [20] Simon, L.T., Ricaurte, G.A. and Forno, L.S. (1989) Chronic idiopathic ataxic neuropathy: neuropathology of a case. Acta Neuropathol., 79: 104107.
Neurology
and Neurosurgery
96 (1994) 191-196
Case report
Hereditary sensory and autonomic neuropathy Adriana Marbin?*,
with ataxia and late onset
Giovanni Paves?, Giovanna Cenacchib, Anna Mazzucchi”, Paola Predab, Franc0 Gemignani” “Institute of Neurology, University of‘ Parma,via de1 Quartierc, 4. I-43100 Parma. Italy. ‘Institute of Electron Microscopy, University of Bologna, Bologna, Italv Received
21 September
1993; revised
6 December
1993; accepted
13 December
1993
Abstract
We report two brothers affected by a dominantly inherited form of hereditary sensory and autonomic neuropathy (HSAN), characterized by clinical features of sensory ataxia, and by late onset in the 6th decade. Sural nerve biopsy in the proband showed almost complete loss of myelinated fibers, and relative sparing of unmyelinated fibers. This family showed an atypical presentation of HSAN, which is usually characterized by acrodystrophic manifestations of infantile or juvenile onset. Although a few reports of HSAN presenting with late onset and/or ataxia appeared, this is the first report of a family with dominant HSAN characterized by late onset sensory ataxia. Key words:
Hereditary sensory neuropathy;
Ataxia; Nerve biopsy
1. Introduction The classification of hereditary sensory and autonomic neuropathies (HSAN) is based on a combination of the clinical and genetic features [1,2]. We report a family with HSAN of dominant type characterized by late onset sensory ataxia, which represents a further clinical variant.
2. Case reports Case 1 A 66-year-old man complained of unsteady gait, with a tendency to widen the stepping base at the age of 60 years. Unsteadiness was worse in the dark. In the last 2 years he reported that he had often to hold on to something in order to stand erect, as if he had ‘stepped into a hole’. For about 1 year he had been feeling a tingling sensation in his legs, especially during the night. He also reported frequent dizziness when getting up in the morn-
*Corresponding
author.
Fax: (0521) 282776.
0303-8467/94/$7.00 0 1994 Elsevier SSDI 0303-8467(93)EOl 15-8
Science B.V. All rights
reserved
ing, slow digestion, tendency to constipation, slow start in urinating, and reduced foot perspiration. Neurological examination showed normal cranial nerve function, apart from deafness, and normal limb muscle bulk and strength. There was moderate dysmetria in the finger-to-nose and heel-to-knee tests when visual control was suppressed. Deep tendon reflexes were absent in the ankles. Light touch sensation was mildly reduced in the feet. Vibration sense was moderately reduced in the lower limbs, especially in the knees. Position sense was markedly impaired in the extremities. Tcmperature sensation was diffusely impaired throughout the body. Disturbance of pain sensation was distributed in a similar pattern, and the stimuli were perceived with delay and with an unpleasant quality. Standing was maintained with widened stepping base, and was impossible without visual control. Gait was wide-based, with inability to tandem walk. Extensive laboratory investigations gave normal results except for a slight increase in serum IgA (393 mg/ 100 ml; normal 116-374). Audiometric study showed sensorineural hearing loss. Chest x-ray, EEG, CSF examination, CT scan and MRI of the brain, and myelogram were normal. Autonomic function tests provided
2
3
4
6
5
I
9
q
affected
normal
00
a
by history
III@
to
probably affccttd
11
12
13
14
15
16
(deceased)
normal by examination
Fig. 1. Family tree, showing autosomal dominant inheritance.
abnormal values: orthostatic hypotension 30 mm Hg (normal, I 10); handgrip test 0 mm Hg (normal, 2 16 mm Hg); Valsalva ratio 1.08 (normal, 2 1.2 1); deep breathing test 2.5 beats/min (normal, 215); lying-to-standing test 1.00 (normal, ~1.04) (methods and normal values according to Ewing and Clarke [3]). Neurophysiological study showed normal EMG findings in the distal muscles of the limbs. Examination of the sensory nerves showed extremely reduced or absent Table 1 Nerve conduction studies Case 1 Motor nerves _ Peroneal amplitude (2 3 mV) distal latency (I 5.5 ms) conduction velocity (2 43 m/s) Median amplitude (->6 mV) distal latency (< 4.5 ms) conduction velocity (2 49 m/s) Sensory nerves - Sural amplitude (> 6 ,A’) conduction velocity (> 46 m/s) - Median amplitude (2 4.5 pV) conduction velocity (2 48 m/s) Ulnar amplitude (2 4 PV) conduction velocity (> 47 m/s)
Case 2
R
L
R
L
11 3.8 44.2
7.5 3.6 42.6
7.5 3.1 47
7 2.9 46.7
10 4.3 46.9*
NR* -
0.5* 35.9*
NR* -
1.2* 28.7*
1* 40.3*
2.5* 30.8*
R = right; L = left; NR = no response; * = abnormal.
l* 43.4%
sensory action potentials (SAP) and reduced conduction velocities (CV), whereas there were only minor alterations in the motor nerves (Table 1). Median and peroneal somatosensory evoked potentials were normal. A sympathetic skin response of low-normal amplitude (0.2 mV) was elicited in the lower limbs. Case 2 The patient’s brother, 62-year-old, also reported unbalance in the last few years. Neurologic examination revealed marked sensory ataxia, absent Achilles tendon reflexes, and deficit in all sensation modalities in the lower limbs. EMG of the limb muscles was normal. Electrophysiological findings were normal for the motor nerves, with extremely reduced amplitude or absence of the SAP and slowed CV of sensory nerves (Table 1). Sympathetic skin response was of borderline amplitude (0.1 mV). Family study (Fig. I) Unbalance with onset around the 6th decade was reported also in the father and in another brother, both deceased. The patients’ sons, aged 18 to 40, were examined but no symptoms or signs of neuromuscular disorders were detected. Electrophysiological study and autonomic function tests were performed in the 3S-year-old daughter of patient 2, with negative results. Neuropathological study A combined biopsy of the sural nerve 5 cm above the lateral malleolus and of the peroneus brevis muscle was
A. Marbini et al. IClinical
Fig. 2. Sural nerve biopsy:
semithin
section
Neurology
showing
and Neurosurgery
96 (1994)
severe and diffuse myelinated
193
191-196
fiber loss (toluidine
blue stain. x400)
perfor med in the case 1, and examined with standard methc Fds for histology, histochemistry, and electron microscc ‘PY [41.
The sural nerve consisted of 11 fascicles with an increased total fascicular area of 1.673 mm2 (nom nal, 8.4k 1.6 fascicles, and transverse fascicular area of
Fig. 3. Sural nerve biopsy: semithin
fibers with excessively
section showing
a few surviving
myelinated
thin myelin sheaths (toluidine
blue stain. xl 000).
Fig. 4. Sural nerve biopsy: unmyelinated (electron microscopy, Xl I 000)
fibers with myelinoid
bodies (arrows)
0.842 f 0.218 mm2, according to Nukada et al. [5]). Semithin sections and morphometric study showed extremely severe loss of myelinated fibers of all diameters (622/ mm2) (Fig. 2) with slight difference in proportion between small (47%) and large fibers (53%). Occasional surviving fibers showed thin myelin sheaths, active axonal degeneration, and regeneration (Fig. 3). Unmyelinated fiber population seemed to be relatively less involved (7772/mm2; control 32 000/mm2), however, aspects of axon damage (Fig. 4) and frequent stacks of flattened Schwann cell processes and collagen pockets suggesting previous fiber degeneration (Fig. 5) were present. Search for amyloid was negative. Only 13 teased fibers, which showed normal features, could be isolated due to severe myelinated fiber loss. Muscle biopsy iindings were normal.
3. Discussion A diagnosis of HSAN was established in this family, despite atypical features, as we could rule out a few other inherited diseases which may produce similar clinical manifestations. Familial amyloid polyneuropathy type 1
into the axoplasm.
Endoneurial
collagen
fibrils are densely packed
is also characterized by sensory loss and autonomic dysfunction; however, pain and temperature sensation, rather than proprioception, is selectively involved, and ocular abnormalities are usually prominent [6]. Amyloid was not present in the nerve biopsy of our proband. In multiple system atrophy, autonomic dysfunction is associated with clinical and neuroradiological evidence of extrapyramidal or cerebellar involvement, not seen in our patients, whereas peripheral nerve involvement, if present, is usually subclinical [7]. HSAN has been classified by Dyck [I], mainly based on mode of inheritance, into HSAN type I (dominant autosomal), HSAN type II (recessive), HSAN type III (familial dysautonomia), HSAN type IV (diffuse absence of pain sensation with anhidrosis), HSAN type V (absence of pain sensation and anhidrosis with selective loss of small fibers). In addition, a family with X-4inked recessive HSAN has been reported [8]. As clinical manifestations are not homogeneous within the genetic categories of HSAN, further subgroups of HSAN have been proposed on clinical grounds [2]. The family reported here, however, does not fit into current classifications of HSAN, as it was characterized by exceptionally late onset (not before the 6th decade), and by sensory ataxia.
A. Marbini et al. IClinical Neurology and Neurosurgery 96 (1994)
Fig. 5. Sural nerve biopsy:
numerous
multilamellar
stacks
(arrows)
instead of the acrodystrophic manifestations which are usually seen in HSAN. Despite these atypical symptoms, this form could be classified as HSAN type I because of the hereditary transmission of likely dominant type. The other varieties of HSAN could be excluded as they are congenital and usually show a significant reduction of the fascicular area [5]. Predominantly ataxic manifestations have been described in rare cases of dominant [9] and recessive [lo] or sporadic [5,11] HSAN; in the two brothers described by Staal and Mechelse [lo] there was a late onset in the 5th to 6th decade. Previous cases of dominant and sporadic HSAN showed association with deafness [9,12,13,14] and increased serum IgA level [15,16]. Acrodystrophic symptoms are not constant in HSAN I [l], and in our patients the persistence of a certain amount of unmyelinated nociceptive fibers may have contributed to their prevention. Even though onset of HSAN I is usually in the 2nd to 3rd decade and no families with onset as late as in our case have been described, there is however great variability in the onset and progression of the disease [l]. Our morphometric findings of profound loss of myelinated fibers with relative preservation of unmyelinated fibers did not coincide with previous data
and collagen
pockets
195
191-196
(arrowheads)
(electron
microscopy,
x40 800).
in HSAN I by Dyck [l] (loss of unmyelinated fibers and small myelinated fibers) and by Danon and Carpenter [ 171(uniform loss for every fiber type), rather resembling the pathologic features of HSAN II [5,18]. In view of the limited number of cases described in the literature, a precise clinical and morphological characterization of HSAN is still problematic. This report emphasizes the occurrence of HSAN with unusual features of sensory ataxia of late onset, a clinical variant not considered in current classifications [1,2]. Although the present family exhibited a likely dominant inheritance, a similar clinical pattern seems to occur also in recessive [lo] and sporadic [5,11] HSAN. In addition, it should be noted that this form is phenotypically identical to the pattern of late onset sensory ataxia of the so-called chronic idiopathic ataxic neuropathy [19,20], in which, however, a genetic basis has not been advanced.
References [I] Dyck, nantly Dyck,
P.J. (1984) Neuronal atrophy and degeneration predomiaffecting peripheral sensory and autonomic neurons. In: P.J., Thomas, P.K.. Lambert. E.H. and Bunge R. (Eds),
196
il. Marbini
ef al. I c’limcul
Neurologv
Peripheral Neuropathy, vol. 2, W.B. Saunders, Philadelphia, PA, pp. 1551-1599. [2] Donaghy, M., Hakin, R.N., Bamford, J.M., Garner, A., Kirkby, G.R., Noble, B.A., Tazir-Melboucy, M., King, R.H.M. and Thomas, P.K. (1987) Hereditary sensory neuropathy with neurotrophic keratitis. Description of an autosomal recessive disorder with a selective reduction of small myelinated nerve fibres and a discussion of the classification of the hereditary sensory neuropathies. Brain, 110: 563-583. [3] Ewing, D.J. and Clarke, B.F. (1982) Diagnosis and management of diabetic autonomic neuropathy. Br. Med. J., 285: 916-918. [4] Gemignani, F., Guidetti, D., Bizzi, P., Preda, P., Cenacchi, G. and Marbini, A. (1992) Peroneal muscular atrophy with hereditary spastic paraparesis (HMSN V) is pathologically heterogeneous. Acta Neuropathol., 83: 196201. [5] Nukada, K., Pollock, M. and Haas, L.F. (1982) The clinical spectrum and morphology of type II hereditary sensory neuropathy. Brain, 105: 647-665. [6] Hersch, MI. and McLeod, J.G. (1987) Peripheral neuropathy associated with amyloidosis. In: Vinken, P.J., Bruyn, G.W., Klawans, H.L. and Matthews, W.B. (Eds.), Handbook of Clinical Neurology, vol. 5 1, Neuropathies, Elsevier Science Publishers B.V., Amsterdam, pp. 413428. [7] Bannister, R. (1988) Clinical features of autonomic failure. A. Symptoms, signs, and special investigations. In: Bannister, R. (Ed.), Autonomic Failure, Oxford University Press, Oxford. pp. 267-281. [8] Jestico, J.V., Urry, P.A. and Efphimiou, J. (1985) An hereditary sensory and autonomic neuropathy transmitted as an X-linked recessive trait. J. Neurol. Neurosurg. Psychiat., 48: 1259-1264. [9] Robinson, G.C., Jan, J.E. and Miller, R.J. (1977) A new variety of hereditary sensory neuropathy. Hum. Genet., 35: 153-161.
und Neurosurger.v
Yt, (1994)
IYI-
100
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