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Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): Clinical and neuropathological features of a Japanese family
Journal of the Neurological Sciences 158 (1998) 30–37
Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): Clinical and neuropathological features of a Japanese family a, b a a b ,c d a Y. Sekijima *, S. Ohara , S. Nakagawa , K. Tabata , K. Yoshida , H. Ishigame , Y. Shimizu , b N. Yanagisawa a
b
Department of Medicine ( Neurology), Saku Central Hospital, Usuda, Japan Department of Medicine ( Neurology), Shinshu University School of Medicine, Matsumoto, Japan c Division of Clinical Genetics, Shinshu University Hospital, Matsumoto, Japan d Department of Pathology, Saku Central Hospital, Usuda, Japan Received 22 October 1997; accepted 4 December 1997
Abstract We report clinicopathological features of a Japanese family with hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA). Four affected members from a single generation were examined. They shared common clinical features, including insidious onset in teenage, slowly progressive cerebellar ataxia, amyotrophy, sensory disturbance, and dementia. In addition, all the patients showed hypoalbuminemia and hyperlipidemia and a marked atrophy of the cerebellum on magnetic resonance images. Autopsy of the proband revealed a severe loss of Purkinje cells, degeneration of posterior columns and spinocerebellar tracts of the spinal cord, and a marked loss of myelinated and unmyelinated fibers in the peripheral nerves. We consider that HMSNCA is a distinct form of hereditary multisystem neuronal degeneration. 1998 Elsevier Science B.V. Keywords: Spinocerebellar degeneration (SCD); Hereditary motor and sensory neuropathy (HMSN); Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA); Friedreich ataxia; Cerebellar atrophy; Hypoalbuminemia; Hyperlipidemia
1. Introduction Recently, families with sensorimotor neuropathy and cerebellar atrophy with hypoalbuminemia have been increasingly reported in Japan [6,8,10–12,16,22]. They share such common clinical features as autosomal recessive inheritance, early onset in teenage, cerebellar ataxia, dementia, polyneuropathy. Although they were initially considered a variant form of Friedreich ataxia [4,9,22], subsequent clinical studies, including five Japanese families have led Fukuhara et al. [6] to propose a new *Corresponding author. Department of Medicine (Neurology), Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. Tel.: 181 263 372673; fax: 181 263 340929; e-mail: [email protected] 0022-510X / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00103-8
disease entity, hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA). However, neuropathological features of HMSNCA and its genetic defect are still unknown, and the nosological position of HMSNCA has not been settled yet. Here, we report about clinical features of a new Japanese family consistent with HMSNCA and describe the postmortem findings of the most severely affected patient.
2. Patient histories The individuals studied were 6 Japanese siblings from nonconsanguineous healthy parents, and 4 of them were affected. Other family members had no clinical symptoms (Fig. 1).
Y. Sekijima et al. / Journal of the Neurological Sciences 158 (1998) 30 – 37
Fig. 1. Pedigree of family. Squares denote males, circles denote females; blackened symbols denote affected individuals, and open symbols unaffected individuals. Deceased individuals are marked with a slash, double line indicate consanguineous marriage.
2.1. Patient 1 ( III-1) The patient was a 63-year-old woman. She was the product of a full-term pregnancy, normal delivery and had normal developmental milestones. At age 10, she was observed to have gait disturbance. At around age 15, coarse tremor appeared in the hands while writing or eating. Several years later, dysarthria, muscle weakness and sensory disturbance of the limbs were also noticed. These symptoms slowly progressed and she became wheelchair-bound by age 30. At age 53, the findings of a physical examination were unremarkable except for edema in her lower limbs. On neurological examination, she was moderately demented with a Mini-Mental-State Examination (MMSE) score of 20. Her extraocular movements were moderately limited in all directions with horizontal gaze-evoked nystagmus. Oral dyskinesia, ataxic speech, and choreic movement of upper limbs were evident. The distal extremities showed combined claw and ape hands
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and stork-leg appearance. Distal dominant muscle atrophy and weakness, sensory disturbance of glove and stocking type, limb and truncal ataxia, and generalized areflexia were also observed (Table 1). Routine blood studies showed a decreased total protein and albumin and increased total cholesterol, triglyceride and b-lipoprotein in the serum (Table 2). The serum vitamin B 1 , B 6 , B 12 , and E were normal. The amino acid analyses in blood and urine were normal. The activities of lysosomal enzymes in leukocytes, including arylsulfatase A, arylsulfatase B, agalactosidase, b-galactosidase, a-mannosidase, a-fuccosidase, b-hexosaminidase A, b-hexosaminidase B, and bglucocerebrosidase, were in the normal ranges. The chest roentgenogram (Xp) and electrocardiogram (ECG) were normal. The electroencephalogram (EEG) showed a diffuse increase of u and d waves in the awake recording, and some d bursts during photostimulation. The needle electromyogram (EMG) of the upper and lower extremities showed reduced recruitment and long-duration, polyphasic potentials. The median nerve motor conduction velocity (MCV) was 41.7 m / s (normal range 47–60 m / s). Compound-muscle action potentials (CMAP) of lower limbs could not be obtained (Table 2). The brain-computed tomography (CT) and magnetic resonance images (MRI) disclosed a severe cerebellar atrophy and a mild atrophy of the cerebral hemisphere (Fig. 2A,B). Rectal biopsy revealed no evidence of storage diseases. Duplication in the PMP22 gene, which is frequently seen in patients with HMSN IA [21], was not detected by fluorescence in situ hybridization (FISH). Friedreich disease, dentatorubropallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD) were also ruled out by the polymerase chain reaction (PCR) analysis for GAA repeat expansion in X25
Table 1 Summary of clinical symptoms Individuals
Patient 1 (III-1)
Patient 2 (III-2)
Patient 3 (III-5)
Patient 4 (III-6)
Age, sex Age at onset Age confined to wheelchair Initial symptom
63, F 10 years 30 years Gait disturbance
62, M 9 years 40 years Gait disturbance
51, M 12 years 41 years Gait disturbance
Mental impairment Extraocular movements restriction Horizontal nystagmus Scanning speech Truncal ataxia Limb ataxia Intentional tremor Choreic movement Fasciculation Muscle weakness Sensory disturbance Deep reflexes Babinski’s sign Deformity of extremities
11 1 11 11 11 11 1 1 2 11 11 Absent Negative 11
111 1 11 111 111 111 111 2 2 111 111 Absent Negative 111
54, M 6 years 40 years Gait disturbance dysarthria 11 1 1 11 11 11 11 2 1 11 11 Absent Negative 11
None: 2, mild: 1, moderate: 11, severe: 111.
11 1 1 11 11 11 11 1 1 11 11 Absent Negative 11
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Table 2 Summary of biochemical data and neurophysiological examinations Individuals
Patient 1 (III-1)
Patient 2 (III-2)
Patient 3 (III-5)
Patient 4 (III-6)
Normal range
Total protein (g / dl) Albumin (g / dl) Total cholesterol (mg / dl) Triglyceride (mg / dl)
5.9 2.1 283 242
6.7 2.6 266 171
6.5 3.3 245 416
5.5 2.1 296 123
6.5–8.2 3.8–5.8 130–220 50–150
MCV: Median n (m / s) Ulnar n (m / s) Tibial n (m / s)
29.9 n.d. n.d.
22.3
41.7 n.d.
30.3 n.d.
n.d.
47–60 49–68 41–61
Needle EMG
Neurogenic
Neurogenic
Neurogenic
Neurogenic
MCV, motor nerve conduction velocity, EMG, electromyography, n.d., not detected.
[2], CAG repeat expansion in DRPLA gene [15,19], and in MJD1 [13], respectively.
2.2. Patient 2 ( III-2) (the proband) The patient was a 62-year-old man. He was born after normal pregnancy and delivery, and his developmental milestones were normal. After graduating from elementary school, he engaged in farming. His initial symptom was ataxic gait beginning at age 9. Dysarthria, limb ataxia, muscle weakness, and sensory disturbance of extremities followed several years later, all of which gradually worsened. When he was 40 years old, he became wheelchairbound, and had difficulties in eating because of tremor of the hands. At age 53, auditory hallucination and personality change appeared, and these symptoms progressed gradually. Since age 60, he was able to speak only very simple words and remained bedridden. At age 61, he was hospitalized because of severe diarrhoea and vomiting. On examination, he was markedly emaciated and his lower extremities were edematous. His major joints were contracted in a flexed position. Neurologically, he was awake
and alert, but could not obey any verbal or written simple command. His utterance was limited to occasional monosyllabic voices, which were very tremulous. A severe resting tremor of the head, jaw, tongue, and bilateral upper extremities continuously appeared while he was awake. He exhibited claw and ape hand and stork-leg appearance in association with a severe muscle atrophy. There was no voluntary movement, and deep tendon reflexes were absent (Table 1). The laboratory examinations showed marked hypoalbuminemia, but the thyroid, liver and renal functions were normal. The amino acid analysis in blood and urine, and lysosomal enzymes in leukocytes were all normal. Chest Xp showed mild cardiomegaly (cadiothoracic ratio 58.0%), but ECG was normal. On the surface EMG, 4 Hz phasic reciprocal grouped discharges were observed in the muscles of the neck and upper extremities. Median nerve MCV was 29.9 m / s. CMAPs could not be obtained in muscles innervated by ulnar and tibial nerves. Sensory nerve action potentials of the median, ulnar, and sural nerves could not be obtained (Table 2). EEG was normal. Brain CT and MRI disclosed a severe cerebellar atrophy and moderate enlargement of
Fig. 2. Brain T1-weighted magnetic resonance images of patient 1 (A, B), patient 2 (C, D), patient 3 (E, F), and patient 4 (G, H) showing severe atrophy of the cerebellum.
Y. Sekijima et al. / Journal of the Neurological Sciences 158 (1998) 30 – 37
the ventricles of the brain (Fig. 2C,D). He died of acute heart failure at age 62 and an autopsy was performed 2 h postmortem.
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Their serum total protein, albumin, total cholesterol, and triglyceride were within the normal range. Their parents died at age 85 from nonneurological causes, and reportedly they had had no neuromuscular symptoms.
2.3. Patient 3 ( III-5) The patient was a 54-year-old man. His developmental milestones were normal. Ataxic gait and dysarthria appeared when he was 6 years old. He noticed intention tremor at age 14. Weakness and sensory disturbance also appeared about age 20, and he became wheelchair-bound at age 40 because of severe gait ataxia. On examination at age 45, he had edema of the lower limbs. Otherwise, his general examination was normal. He showed moderate dementia (MMSE 18), limitation in vertical and horizontal extraocular movements, horizontal gaze-evoked nystagmus, oral dyskinesia, scanning speech, head tremor and intentional tremor of the upper limbs. He exhibited claw and ape hand deformity as well as stork-leg appearance. Distal-dominant muscle atrophy and weakness with fasciculation, glove and stocking-type sensory disturbance, limb and truncal ataxia, and generalized areflexia were also evident (Table 1). The laboratory examinations showed no abnormal findings except for hypoproteinemia, hypoalbuminemia, and hyperlipidemia. Ulnar MCV was 30.3 m / s (normal range 49–68 m / s), and CMAPs of the lower limbs could not be obtained (Table 2). The CT and MRI findings of the brain were very similar to those of patients 1 and 2 (Fig. 2E,F).
2.4. Patient 4 ( III-6)
3. Autopsy findings of patient 2 The postmortem examination showed a cachectic old man (157.5 cm, 36.2 kg) with prominent scoliosis and contractures of the elbow, wrist, hip, knee and ankle joints. Adenoma in thyroid, bilateral pleural effusion, multiple liver cysts, and neurinoma of cauda equina were noted. His visceral organs were otherwise unremarkable. The unfixed brain weighed 1100 g. The leptomeningeal and basal arteries were unremarkable. The cerebellum was markedly atrophic with a relatively preserved volume of the basis pontis (Fig. 3). The spinal cord and anterior nerve roots appeared atrophic with a loss of cervical and lumbar enlargement. Coronal sections of the cerebrum revealed moderate dilatation of the ventricular system. The brain, spinal cord, and peripheral nerves were fixed in 10% formalin and tissue blocks from various portions of the central nervous system were embedded in paraffin. Thin sections were cut and stained with hematoxylin eosin, ¨ Kluver-Barrera stain for myelin, and Bodian method for staining axon. Immunohistochemical studies were performed with the following primary antibodies and speciesspecific biotinated secondary antibodies; mouse monoclonal antiamyloid b protein 4D12 (a kind gift from Dr Kametani, 1:1000), rabbit polyclonal anti-tau (Sigma, 1:1000), mouse monoclonal antiubiquitin (Chemicon,
The patient was a 51-year-old man, the youngest brother of the siblings. He was born after normal pregnancy and delivery. He noticed gait disturbance at age 12, and intention tremor at age 14. Muscle weakness and sensory disturbance appeared in his twenties. At age 41, he became unable to walk because of severe ataxia and was admitted to the Saku Central Hospital. His physical and neurological findings were essentially identical to those of his brother (patient 3); including edema of lower limbs, moderate dementia (MMSE 23), restricted vertical and horizontal extraocular movements, horizontal gaze-evoked nystagmus, scanning speech, head tremor, choreic movement of the upper limbs, claw and ape hand deformity, stork-leg appearance, muscle atrophy and weakness, glove and stocking-type sensory disturbance, limb and truncal ataxia, and generalized areflexia (Table 1). The laboratory and radiological findings of the brain were very similar to those of patients 1, 2, and 3 (Table 2, Fig. 2G,H).
2.5. Asymptomatic individuals ( III-3, III-4, and their parents) These individuals (III-3, III-4) showed no abnormal findings in the general and neurological examinations.
Fig. 3. Macroscopic appearance of the brain of patient 2 showing severe atrophy of the cerebellum with a relatively preserved volume of the basis pontis.
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1:1000), rabbit polyclonal antiubiquitin (Sigma, 1:10), rabbit polyclonal anti-GFAP (DAKO, 1:800), and rabbit polyclonal anti-prion protein (a kind gift from Dr Kitamoto, 1:500). The hydrolytic autoclaving method [14] was used in prion immunohistochemistry. The reaction products were visualized in the Streptavidin method with DAB as chromogen. The sections from pathologically diagnosed Alzheimer’s disease were used as positive controls for b protein and tau immunohistochemistry and those from patients with Creutzfeldt¨ Jakob disease and Gerstmann-Straussler-Scheinker disease for prion immunohistochemistry. Replacement of the antibodies with the corresponding normal animal serum did not yield specific staining pattern. Histologically, the cerebrum showed a mild loss of pyramidal neurons in the deepest layer of the frontal and temporal cortices, accompanied by the regional appearance of hypertrophic astrocytes (Fig. 4A). There were no senile changes. The cerebral white matter showed mild gliosis. The striatum, globus pallidus and subthalamic nucleus were unremarkable. In the thalamus and hypothalamus, there was diffuse gliosis without obvious loss of neurons. The nucleus basalis of Meynert was well populated. The cerebellum showed a severe loss of cerebellar Purkinje cells with their occasional complete disappearance in the individual folium (Fig. 4B). This was accompanied by proliferation of astrocytes and overall thinning of the molecular layer. The dentate nucleus showed an increase in the number of glial cell nuclei but the dentate neurons were well preserved without a ‘grumose’ degeneration (Fig. 4C). The dentate hilus and superior cerebellar peduncles were intact. The midbrain at the level of oculomotor fasciculus appeared normal, including the substantia nigra and red nucleus. In the pons, the tegmentum including the locus coeruleus, pontine nuclei and transverse fibers were all preserved. The nucleus facialis, ambiguus, hypoglossus, dorsal vagal nuclei, and solitary nuclei were unremarkable. The inferior olivary nucleus revealed a mild neuronal loss, proliferation of hypertrophic astrocytes and gliosis in the hilus. In the spinal cord, the gracile fasciculus and spinocerebellar tracts showed myelin parlor (Fig. 4D). The anterior horns were moderately depleted of neurons, which was most apparent in the thoracic and lumbar enlargement (Fig. 4E). The Clarke’s columns showed a moderate loss of neurons. The intermediolateral nuclei of the thoracic cords in the spinal cords were intact. In the dorsal root ganglion, there was a moderate loss of neurons, and some residual nodules were observed (Fig. 4F). The sural nerve showed a nearly complete loss of myelinated fibers with endoneurial fibrosis (Fig. 4G). On electron-microscopic (EM) examination, the number of unmyelinated fiber was greatly reduced (Fig. 5). The vagus nerve and superior cervical ganglion were normal. The skeletal muscles including biceps brachii and quadriceps femoris showed grouped atrophy associated with marked lipofibromatosis. We summarized neuropathological findings in Table 3 (per author).
4. Discussion In this family, the mode of inheritance was compatible with autosomal recessive. All affected siblings presented with gait disturbance as an initial symptom in childhood. The late clinical manifestations in adolescence included limb and truncal ataxia, scanning speech, extraocular movements restriction, horizontal gaze-evoked nystagmus, intention tremor and / or choreic movement of the head and upper extremities, distal dominant amyotrophy and sensory disturbance of all modalities. Dementia was also a common feature which developed after their twenties. All of these symptoms progressed gradually, and the patients became wheelchair-bound because of severe ataxia after 20–30 years from the onset of symptoms. Furthermore, hypoalbuminemia and cerebellar atrophy were common laboratory and radiological features found in all the patients. Constellation of these clinical features does not match any previously established type of HMSN [3] or hereditary SCD [7], but was essentially identical to those of HMSNCA reported by Fukuhara et al. [6]. The autopsy findings of the present case was characterized by a severe cerebellar cortical degeneration with well-preserved dentate and pontine neurons and their efferents. These features are well in accord with imaging studies invariably showing a severe cerebellar atrophy in all the affected siblings. Moreover, our case showed degenerations in the extracerebellar system. The spinal cord showed a moderate neuronal loss in the anterior horn and a degeneration of the anterior roots, which may be responsible for marked amyotrophy seen in this patient from the early stage of the illness. The Clarke’s nuclei and posterior spinocerebellar tract was also affected. The dorsal root ganglion (DRG) showed moderate neuronal loss. However, the posterior columns and sural nerve showed a severe myelinated fiber loss, suggesting the occurrence of dying back processes both in the central and peripheral processes of the DRG neurons. In the studies of 5 families of HMSNCA, Fukuhara et al. reported a relative sparing of unmyelinated axons in the biopsied peripheral nerves [6]. EM studies of the sural nerve of our patient demonstrated a marked depletion of unmyelinated axons as well, suggesting that the unmyelinated sensory axons would be eventually involved in this disease processes. The cerebral cortex of our patient was unremarkable except for a mild neuronal loss and appearance of hypertrophic astrocytes in the deeper layers, and the cerebral white matter showed mild gliosis. The significance of these findings, whether it may have related to dementia seen early in the clinical course of the patients or secondary acquired lesions, is unclear and we should wait for an accumulation of further autopsy studies. Unaffected structures to be noted were the striatonigral system, thalamus, cranial nerve nuclei, and autonomic ganglia. The topological distributions of the lesions described above are different from any previously known forms of spinocerebellar atrophy, especially those affecting the
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Fig. 4. (A–G) Pathological findings of patients 2. (A) GFAP immunohistochemistry of the frontal cortex showing the appearance of hypertrophic astrocytes in the deeper cortical layer and the adjacent white matter. 3100; (B) The cerebellum. Severe depletion of Purkinje cells is evident. H.E. 340; (C) The dentate nucleus. Neurons are well preserved. H.E. 380; (D) The thoracic spinal cord showing myelin parlor in the posterior spinocerebellar tracts and ¨ posterior columns. Kluver-Barrera 32.6; (E) The lumbar spinal cord showing marked depletion of anterior horn cells. Arrowheads indicate anterior median ¨ fissure. Kluver-Barrera 325; (F) The lumbar dorsal root ganglion showing moderate neuronal loss and scattered residual nodules. H.E. 390; (G) The epon embedded semithin plastic section of sural nerve showing nearly complete loss of myelinated fibers. No myelin debris is found in the endoneurium. Toluidine blue stain 3200.
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Y. Sekijima et al. / Journal of the Neurological Sciences 158 (1998) 30 – 37
Fig. 5. Electron micrograph of sural nerve illustrating the presence of numerous bands of Bungners and of collagen pockets in the endoneurium. Unmyelinated axons are greatly reduced in number. 312.000.
extracerebellar system, such as multisystem atrophy, Friedreich ataxia, Machado-Joseph disease, or DRPLA. Patients with similar clinical features to ours were previously reported under the title of atypical Friedreich ataxia [4,22]. But in Friedreich ataxia, in contrast to our patient, no significant lesions are found in the Purkinje cells while the dentate nucleus is often involved [17,20]. The present case does seem to bear a significant resemblance to Biemond ataxia [1,18], a rare form of spinocerebellar ataxia which has now been classified as SCA4 [5]. The autopsy findings of SCA4 consisted of degeneration of cerebellar Purkinje cells, DRG neurons, posterior column, and peripheral nerve [1,18], close to those found in our patient. However, amyotrophy and anterior horn cell degeneration were not described in SCA4. Furthermore, such clinical features commonly recognized in our affected siblings as early onset in teenage, presumable autosomal recessive inheritance, dementia, and hypoalbuminemia are not the features described in SCA4. Based on our clinical and pathological findings, it is likely that this disease belongs to a hitherto undescribed form of hereditary multisystem neuronal degeneration. Exact classification of this disease should rest on future molecular genetic studies.
References Table 3 Distribution of neuronal loss or degeneration Cerebral cortex Cerebral white matter Hippocampus Thalamus Subthalamic nucleus Hypothalamus Striatum Globus pallidus Nucleus basalis of Meynert Purkinje cell Dentate nucleus Superior cerebellar peduncles Red nucreus Substantia nigra Locus ceruleus Pontine nuclei Cranial nerve nuclei Inferior olivary nuclei Pyramidal tract Faciculus gracilis Faciculus cuneatus Spinocerebellar tracts Clarke’s columns Intermediolateral colmuns Anterior horn Anterior roots Posterior roots Dorsal root ganglion Sural nerve Vagus nerve Superior cervical ganglion None: 2, mild: 1, moderate: 11, severe: 111.
1 (Deeper layer) 1 2 2 2 2 2 2 2 111 2 2 2 2 2 2 2 2 1 111 11 111 11 2 11 11 1 11 111 2 2
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[17] Lamarche JB, Lemieux B, Lieu HB. The neuropathology of ‘‘typical’’ Friedreich’s ataxia in Quebec. Can J Neurol Sci 1984;11:592–600. [18] Nachmanoff DB, Segal RA, Dawson DM, Brown RB, De Girolami U. Hereditary ataxia with sensory neuronopathy: Biemond’s ataxia. Neurology 1997;48:273–5. [19] Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, Tanaka Y, Kikushima H, Umino K, Kurosawa H, Furukawa T, Nihei K, Inoue T, Sano A, Komure O, Takahashi M, Yoshizawa T, Kanazawa I, Yamada M. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12 p. Nature Genet 1994;6:14–8. [20] Oppenheimer DR. Brain lesions in Friedreich’s ataxia. Can J Neurol Sci 1979;6:173–6. [21] Patel PI, Roa BB, Welcher AA, Schoener-Scott R, Trask BJ, Pentao L, Snipes GJ, Garcia CA, Francke U, Shooter EM, Lupski JR, Suter U. The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nature Genet 1992;1:159–65. [22] Uekawa K, Yuasa T, Kawasaki S, Makibuchi T, Ideta T. A hereditary ataxia associated with hypoalbuminemia and hyperlipidemia. A variant form of Friedreich’s disease or a new clinical entity? Rinsho Shinkeigaku 1992;32:1067–74 (in Japanese with English abstract).
Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): Clinical and neuropathological features of a Japanese family a, b a a b ,c d a Y. Sekijima *, S. Ohara , S. Nakagawa , K. Tabata , K. Yoshida , H. Ishigame , Y. Shimizu , b N. Yanagisawa a
b
Department of Medicine ( Neurology), Saku Central Hospital, Usuda, Japan Department of Medicine ( Neurology), Shinshu University School of Medicine, Matsumoto, Japan c Division of Clinical Genetics, Shinshu University Hospital, Matsumoto, Japan d Department of Pathology, Saku Central Hospital, Usuda, Japan Received 22 October 1997; accepted 4 December 1997
Abstract We report clinicopathological features of a Japanese family with hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA). Four affected members from a single generation were examined. They shared common clinical features, including insidious onset in teenage, slowly progressive cerebellar ataxia, amyotrophy, sensory disturbance, and dementia. In addition, all the patients showed hypoalbuminemia and hyperlipidemia and a marked atrophy of the cerebellum on magnetic resonance images. Autopsy of the proband revealed a severe loss of Purkinje cells, degeneration of posterior columns and spinocerebellar tracts of the spinal cord, and a marked loss of myelinated and unmyelinated fibers in the peripheral nerves. We consider that HMSNCA is a distinct form of hereditary multisystem neuronal degeneration. 1998 Elsevier Science B.V. Keywords: Spinocerebellar degeneration (SCD); Hereditary motor and sensory neuropathy (HMSN); Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA); Friedreich ataxia; Cerebellar atrophy; Hypoalbuminemia; Hyperlipidemia
1. Introduction Recently, families with sensorimotor neuropathy and cerebellar atrophy with hypoalbuminemia have been increasingly reported in Japan [6,8,10–12,16,22]. They share such common clinical features as autosomal recessive inheritance, early onset in teenage, cerebellar ataxia, dementia, polyneuropathy. Although they were initially considered a variant form of Friedreich ataxia [4,9,22], subsequent clinical studies, including five Japanese families have led Fukuhara et al. [6] to propose a new *Corresponding author. Department of Medicine (Neurology), Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. Tel.: 181 263 372673; fax: 181 263 340929; e-mail: [email protected] 0022-510X / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00103-8
disease entity, hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA). However, neuropathological features of HMSNCA and its genetic defect are still unknown, and the nosological position of HMSNCA has not been settled yet. Here, we report about clinical features of a new Japanese family consistent with HMSNCA and describe the postmortem findings of the most severely affected patient.
2. Patient histories The individuals studied were 6 Japanese siblings from nonconsanguineous healthy parents, and 4 of them were affected. Other family members had no clinical symptoms (Fig. 1).
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Fig. 1. Pedigree of family. Squares denote males, circles denote females; blackened symbols denote affected individuals, and open symbols unaffected individuals. Deceased individuals are marked with a slash, double line indicate consanguineous marriage.
2.1. Patient 1 ( III-1) The patient was a 63-year-old woman. She was the product of a full-term pregnancy, normal delivery and had normal developmental milestones. At age 10, she was observed to have gait disturbance. At around age 15, coarse tremor appeared in the hands while writing or eating. Several years later, dysarthria, muscle weakness and sensory disturbance of the limbs were also noticed. These symptoms slowly progressed and she became wheelchair-bound by age 30. At age 53, the findings of a physical examination were unremarkable except for edema in her lower limbs. On neurological examination, she was moderately demented with a Mini-Mental-State Examination (MMSE) score of 20. Her extraocular movements were moderately limited in all directions with horizontal gaze-evoked nystagmus. Oral dyskinesia, ataxic speech, and choreic movement of upper limbs were evident. The distal extremities showed combined claw and ape hands
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and stork-leg appearance. Distal dominant muscle atrophy and weakness, sensory disturbance of glove and stocking type, limb and truncal ataxia, and generalized areflexia were also observed (Table 1). Routine blood studies showed a decreased total protein and albumin and increased total cholesterol, triglyceride and b-lipoprotein in the serum (Table 2). The serum vitamin B 1 , B 6 , B 12 , and E were normal. The amino acid analyses in blood and urine were normal. The activities of lysosomal enzymes in leukocytes, including arylsulfatase A, arylsulfatase B, agalactosidase, b-galactosidase, a-mannosidase, a-fuccosidase, b-hexosaminidase A, b-hexosaminidase B, and bglucocerebrosidase, were in the normal ranges. The chest roentgenogram (Xp) and electrocardiogram (ECG) were normal. The electroencephalogram (EEG) showed a diffuse increase of u and d waves in the awake recording, and some d bursts during photostimulation. The needle electromyogram (EMG) of the upper and lower extremities showed reduced recruitment and long-duration, polyphasic potentials. The median nerve motor conduction velocity (MCV) was 41.7 m / s (normal range 47–60 m / s). Compound-muscle action potentials (CMAP) of lower limbs could not be obtained (Table 2). The brain-computed tomography (CT) and magnetic resonance images (MRI) disclosed a severe cerebellar atrophy and a mild atrophy of the cerebral hemisphere (Fig. 2A,B). Rectal biopsy revealed no evidence of storage diseases. Duplication in the PMP22 gene, which is frequently seen in patients with HMSN IA [21], was not detected by fluorescence in situ hybridization (FISH). Friedreich disease, dentatorubropallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD) were also ruled out by the polymerase chain reaction (PCR) analysis for GAA repeat expansion in X25
Table 1 Summary of clinical symptoms Individuals
Patient 1 (III-1)
Patient 2 (III-2)
Patient 3 (III-5)
Patient 4 (III-6)
Age, sex Age at onset Age confined to wheelchair Initial symptom
63, F 10 years 30 years Gait disturbance
62, M 9 years 40 years Gait disturbance
51, M 12 years 41 years Gait disturbance
Mental impairment Extraocular movements restriction Horizontal nystagmus Scanning speech Truncal ataxia Limb ataxia Intentional tremor Choreic movement Fasciculation Muscle weakness Sensory disturbance Deep reflexes Babinski’s sign Deformity of extremities
11 1 11 11 11 11 1 1 2 11 11 Absent Negative 11
111 1 11 111 111 111 111 2 2 111 111 Absent Negative 111
54, M 6 years 40 years Gait disturbance dysarthria 11 1 1 11 11 11 11 2 1 11 11 Absent Negative 11
None: 2, mild: 1, moderate: 11, severe: 111.
11 1 1 11 11 11 11 1 1 11 11 Absent Negative 11
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Table 2 Summary of biochemical data and neurophysiological examinations Individuals
Patient 1 (III-1)
Patient 2 (III-2)
Patient 3 (III-5)
Patient 4 (III-6)
Normal range
Total protein (g / dl) Albumin (g / dl) Total cholesterol (mg / dl) Triglyceride (mg / dl)
5.9 2.1 283 242
6.7 2.6 266 171
6.5 3.3 245 416
5.5 2.1 296 123
6.5–8.2 3.8–5.8 130–220 50–150
MCV: Median n (m / s) Ulnar n (m / s) Tibial n (m / s)
29.9 n.d. n.d.
22.3
41.7 n.d.
30.3 n.d.
n.d.
47–60 49–68 41–61
Needle EMG
Neurogenic
Neurogenic
Neurogenic
Neurogenic
MCV, motor nerve conduction velocity, EMG, electromyography, n.d., not detected.
[2], CAG repeat expansion in DRPLA gene [15,19], and in MJD1 [13], respectively.
2.2. Patient 2 ( III-2) (the proband) The patient was a 62-year-old man. He was born after normal pregnancy and delivery, and his developmental milestones were normal. After graduating from elementary school, he engaged in farming. His initial symptom was ataxic gait beginning at age 9. Dysarthria, limb ataxia, muscle weakness, and sensory disturbance of extremities followed several years later, all of which gradually worsened. When he was 40 years old, he became wheelchairbound, and had difficulties in eating because of tremor of the hands. At age 53, auditory hallucination and personality change appeared, and these symptoms progressed gradually. Since age 60, he was able to speak only very simple words and remained bedridden. At age 61, he was hospitalized because of severe diarrhoea and vomiting. On examination, he was markedly emaciated and his lower extremities were edematous. His major joints were contracted in a flexed position. Neurologically, he was awake
and alert, but could not obey any verbal or written simple command. His utterance was limited to occasional monosyllabic voices, which were very tremulous. A severe resting tremor of the head, jaw, tongue, and bilateral upper extremities continuously appeared while he was awake. He exhibited claw and ape hand and stork-leg appearance in association with a severe muscle atrophy. There was no voluntary movement, and deep tendon reflexes were absent (Table 1). The laboratory examinations showed marked hypoalbuminemia, but the thyroid, liver and renal functions were normal. The amino acid analysis in blood and urine, and lysosomal enzymes in leukocytes were all normal. Chest Xp showed mild cardiomegaly (cadiothoracic ratio 58.0%), but ECG was normal. On the surface EMG, 4 Hz phasic reciprocal grouped discharges were observed in the muscles of the neck and upper extremities. Median nerve MCV was 29.9 m / s. CMAPs could not be obtained in muscles innervated by ulnar and tibial nerves. Sensory nerve action potentials of the median, ulnar, and sural nerves could not be obtained (Table 2). EEG was normal. Brain CT and MRI disclosed a severe cerebellar atrophy and moderate enlargement of
Fig. 2. Brain T1-weighted magnetic resonance images of patient 1 (A, B), patient 2 (C, D), patient 3 (E, F), and patient 4 (G, H) showing severe atrophy of the cerebellum.
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the ventricles of the brain (Fig. 2C,D). He died of acute heart failure at age 62 and an autopsy was performed 2 h postmortem.
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Their serum total protein, albumin, total cholesterol, and triglyceride were within the normal range. Their parents died at age 85 from nonneurological causes, and reportedly they had had no neuromuscular symptoms.
2.3. Patient 3 ( III-5) The patient was a 54-year-old man. His developmental milestones were normal. Ataxic gait and dysarthria appeared when he was 6 years old. He noticed intention tremor at age 14. Weakness and sensory disturbance also appeared about age 20, and he became wheelchair-bound at age 40 because of severe gait ataxia. On examination at age 45, he had edema of the lower limbs. Otherwise, his general examination was normal. He showed moderate dementia (MMSE 18), limitation in vertical and horizontal extraocular movements, horizontal gaze-evoked nystagmus, oral dyskinesia, scanning speech, head tremor and intentional tremor of the upper limbs. He exhibited claw and ape hand deformity as well as stork-leg appearance. Distal-dominant muscle atrophy and weakness with fasciculation, glove and stocking-type sensory disturbance, limb and truncal ataxia, and generalized areflexia were also evident (Table 1). The laboratory examinations showed no abnormal findings except for hypoproteinemia, hypoalbuminemia, and hyperlipidemia. Ulnar MCV was 30.3 m / s (normal range 49–68 m / s), and CMAPs of the lower limbs could not be obtained (Table 2). The CT and MRI findings of the brain were very similar to those of patients 1 and 2 (Fig. 2E,F).
2.4. Patient 4 ( III-6)
3. Autopsy findings of patient 2 The postmortem examination showed a cachectic old man (157.5 cm, 36.2 kg) with prominent scoliosis and contractures of the elbow, wrist, hip, knee and ankle joints. Adenoma in thyroid, bilateral pleural effusion, multiple liver cysts, and neurinoma of cauda equina were noted. His visceral organs were otherwise unremarkable. The unfixed brain weighed 1100 g. The leptomeningeal and basal arteries were unremarkable. The cerebellum was markedly atrophic with a relatively preserved volume of the basis pontis (Fig. 3). The spinal cord and anterior nerve roots appeared atrophic with a loss of cervical and lumbar enlargement. Coronal sections of the cerebrum revealed moderate dilatation of the ventricular system. The brain, spinal cord, and peripheral nerves were fixed in 10% formalin and tissue blocks from various portions of the central nervous system were embedded in paraffin. Thin sections were cut and stained with hematoxylin eosin, ¨ Kluver-Barrera stain for myelin, and Bodian method for staining axon. Immunohistochemical studies were performed with the following primary antibodies and speciesspecific biotinated secondary antibodies; mouse monoclonal antiamyloid b protein 4D12 (a kind gift from Dr Kametani, 1:1000), rabbit polyclonal anti-tau (Sigma, 1:1000), mouse monoclonal antiubiquitin (Chemicon,
The patient was a 51-year-old man, the youngest brother of the siblings. He was born after normal pregnancy and delivery. He noticed gait disturbance at age 12, and intention tremor at age 14. Muscle weakness and sensory disturbance appeared in his twenties. At age 41, he became unable to walk because of severe ataxia and was admitted to the Saku Central Hospital. His physical and neurological findings were essentially identical to those of his brother (patient 3); including edema of lower limbs, moderate dementia (MMSE 23), restricted vertical and horizontal extraocular movements, horizontal gaze-evoked nystagmus, scanning speech, head tremor, choreic movement of the upper limbs, claw and ape hand deformity, stork-leg appearance, muscle atrophy and weakness, glove and stocking-type sensory disturbance, limb and truncal ataxia, and generalized areflexia (Table 1). The laboratory and radiological findings of the brain were very similar to those of patients 1, 2, and 3 (Table 2, Fig. 2G,H).
2.5. Asymptomatic individuals ( III-3, III-4, and their parents) These individuals (III-3, III-4) showed no abnormal findings in the general and neurological examinations.
Fig. 3. Macroscopic appearance of the brain of patient 2 showing severe atrophy of the cerebellum with a relatively preserved volume of the basis pontis.
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1:1000), rabbit polyclonal antiubiquitin (Sigma, 1:10), rabbit polyclonal anti-GFAP (DAKO, 1:800), and rabbit polyclonal anti-prion protein (a kind gift from Dr Kitamoto, 1:500). The hydrolytic autoclaving method [14] was used in prion immunohistochemistry. The reaction products were visualized in the Streptavidin method with DAB as chromogen. The sections from pathologically diagnosed Alzheimer’s disease were used as positive controls for b protein and tau immunohistochemistry and those from patients with Creutzfeldt¨ Jakob disease and Gerstmann-Straussler-Scheinker disease for prion immunohistochemistry. Replacement of the antibodies with the corresponding normal animal serum did not yield specific staining pattern. Histologically, the cerebrum showed a mild loss of pyramidal neurons in the deepest layer of the frontal and temporal cortices, accompanied by the regional appearance of hypertrophic astrocytes (Fig. 4A). There were no senile changes. The cerebral white matter showed mild gliosis. The striatum, globus pallidus and subthalamic nucleus were unremarkable. In the thalamus and hypothalamus, there was diffuse gliosis without obvious loss of neurons. The nucleus basalis of Meynert was well populated. The cerebellum showed a severe loss of cerebellar Purkinje cells with their occasional complete disappearance in the individual folium (Fig. 4B). This was accompanied by proliferation of astrocytes and overall thinning of the molecular layer. The dentate nucleus showed an increase in the number of glial cell nuclei but the dentate neurons were well preserved without a ‘grumose’ degeneration (Fig. 4C). The dentate hilus and superior cerebellar peduncles were intact. The midbrain at the level of oculomotor fasciculus appeared normal, including the substantia nigra and red nucleus. In the pons, the tegmentum including the locus coeruleus, pontine nuclei and transverse fibers were all preserved. The nucleus facialis, ambiguus, hypoglossus, dorsal vagal nuclei, and solitary nuclei were unremarkable. The inferior olivary nucleus revealed a mild neuronal loss, proliferation of hypertrophic astrocytes and gliosis in the hilus. In the spinal cord, the gracile fasciculus and spinocerebellar tracts showed myelin parlor (Fig. 4D). The anterior horns were moderately depleted of neurons, which was most apparent in the thoracic and lumbar enlargement (Fig. 4E). The Clarke’s columns showed a moderate loss of neurons. The intermediolateral nuclei of the thoracic cords in the spinal cords were intact. In the dorsal root ganglion, there was a moderate loss of neurons, and some residual nodules were observed (Fig. 4F). The sural nerve showed a nearly complete loss of myelinated fibers with endoneurial fibrosis (Fig. 4G). On electron-microscopic (EM) examination, the number of unmyelinated fiber was greatly reduced (Fig. 5). The vagus nerve and superior cervical ganglion were normal. The skeletal muscles including biceps brachii and quadriceps femoris showed grouped atrophy associated with marked lipofibromatosis. We summarized neuropathological findings in Table 3 (per author).
4. Discussion In this family, the mode of inheritance was compatible with autosomal recessive. All affected siblings presented with gait disturbance as an initial symptom in childhood. The late clinical manifestations in adolescence included limb and truncal ataxia, scanning speech, extraocular movements restriction, horizontal gaze-evoked nystagmus, intention tremor and / or choreic movement of the head and upper extremities, distal dominant amyotrophy and sensory disturbance of all modalities. Dementia was also a common feature which developed after their twenties. All of these symptoms progressed gradually, and the patients became wheelchair-bound because of severe ataxia after 20–30 years from the onset of symptoms. Furthermore, hypoalbuminemia and cerebellar atrophy were common laboratory and radiological features found in all the patients. Constellation of these clinical features does not match any previously established type of HMSN [3] or hereditary SCD [7], but was essentially identical to those of HMSNCA reported by Fukuhara et al. [6]. The autopsy findings of the present case was characterized by a severe cerebellar cortical degeneration with well-preserved dentate and pontine neurons and their efferents. These features are well in accord with imaging studies invariably showing a severe cerebellar atrophy in all the affected siblings. Moreover, our case showed degenerations in the extracerebellar system. The spinal cord showed a moderate neuronal loss in the anterior horn and a degeneration of the anterior roots, which may be responsible for marked amyotrophy seen in this patient from the early stage of the illness. The Clarke’s nuclei and posterior spinocerebellar tract was also affected. The dorsal root ganglion (DRG) showed moderate neuronal loss. However, the posterior columns and sural nerve showed a severe myelinated fiber loss, suggesting the occurrence of dying back processes both in the central and peripheral processes of the DRG neurons. In the studies of 5 families of HMSNCA, Fukuhara et al. reported a relative sparing of unmyelinated axons in the biopsied peripheral nerves [6]. EM studies of the sural nerve of our patient demonstrated a marked depletion of unmyelinated axons as well, suggesting that the unmyelinated sensory axons would be eventually involved in this disease processes. The cerebral cortex of our patient was unremarkable except for a mild neuronal loss and appearance of hypertrophic astrocytes in the deeper layers, and the cerebral white matter showed mild gliosis. The significance of these findings, whether it may have related to dementia seen early in the clinical course of the patients or secondary acquired lesions, is unclear and we should wait for an accumulation of further autopsy studies. Unaffected structures to be noted were the striatonigral system, thalamus, cranial nerve nuclei, and autonomic ganglia. The topological distributions of the lesions described above are different from any previously known forms of spinocerebellar atrophy, especially those affecting the
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Fig. 4. (A–G) Pathological findings of patients 2. (A) GFAP immunohistochemistry of the frontal cortex showing the appearance of hypertrophic astrocytes in the deeper cortical layer and the adjacent white matter. 3100; (B) The cerebellum. Severe depletion of Purkinje cells is evident. H.E. 340; (C) The dentate nucleus. Neurons are well preserved. H.E. 380; (D) The thoracic spinal cord showing myelin parlor in the posterior spinocerebellar tracts and ¨ posterior columns. Kluver-Barrera 32.6; (E) The lumbar spinal cord showing marked depletion of anterior horn cells. Arrowheads indicate anterior median ¨ fissure. Kluver-Barrera 325; (F) The lumbar dorsal root ganglion showing moderate neuronal loss and scattered residual nodules. H.E. 390; (G) The epon embedded semithin plastic section of sural nerve showing nearly complete loss of myelinated fibers. No myelin debris is found in the endoneurium. Toluidine blue stain 3200.
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Y. Sekijima et al. / Journal of the Neurological Sciences 158 (1998) 30 – 37
Fig. 5. Electron micrograph of sural nerve illustrating the presence of numerous bands of Bungners and of collagen pockets in the endoneurium. Unmyelinated axons are greatly reduced in number. 312.000.
extracerebellar system, such as multisystem atrophy, Friedreich ataxia, Machado-Joseph disease, or DRPLA. Patients with similar clinical features to ours were previously reported under the title of atypical Friedreich ataxia [4,22]. But in Friedreich ataxia, in contrast to our patient, no significant lesions are found in the Purkinje cells while the dentate nucleus is often involved [17,20]. The present case does seem to bear a significant resemblance to Biemond ataxia [1,18], a rare form of spinocerebellar ataxia which has now been classified as SCA4 [5]. The autopsy findings of SCA4 consisted of degeneration of cerebellar Purkinje cells, DRG neurons, posterior column, and peripheral nerve [1,18], close to those found in our patient. However, amyotrophy and anterior horn cell degeneration were not described in SCA4. Furthermore, such clinical features commonly recognized in our affected siblings as early onset in teenage, presumable autosomal recessive inheritance, dementia, and hypoalbuminemia are not the features described in SCA4. Based on our clinical and pathological findings, it is likely that this disease belongs to a hitherto undescribed form of hereditary multisystem neuronal degeneration. Exact classification of this disease should rest on future molecular genetic studies.
References Table 3 Distribution of neuronal loss or degeneration Cerebral cortex Cerebral white matter Hippocampus Thalamus Subthalamic nucleus Hypothalamus Striatum Globus pallidus Nucleus basalis of Meynert Purkinje cell Dentate nucleus Superior cerebellar peduncles Red nucreus Substantia nigra Locus ceruleus Pontine nuclei Cranial nerve nuclei Inferior olivary nuclei Pyramidal tract Faciculus gracilis Faciculus cuneatus Spinocerebellar tracts Clarke’s columns Intermediolateral colmuns Anterior horn Anterior roots Posterior roots Dorsal root ganglion Sural nerve Vagus nerve Superior cervical ganglion None: 2, mild: 1, moderate: 11, severe: 111.
1 (Deeper layer) 1 2 2 2 2 2 2 2 111 2 2 2 2 2 2 2 2 1 111 11 111 11 2 11 11 1 11 111 2 2
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