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Motor neuronopathy in Chediak–Higashi syndrome
Journal of the Neurological Sciences 344 (2014) 203–207
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Motor neuronopathy in Chediak–Higashi syndrome S. Mathis a, P. Cintas b, G. de Saint-Basile c, L. Magy d, B. Funalot d, J.-M. Vallat d,⁎ a
Department of Neurology, CHU Poitiers, University of Poitiers, 2 rue de la Milétrie, 86021 Poitiers, France Department of Neurology, CHU Rangueil, 1 avenue J. Poulhès, 31059 Toulouse, France c Unité de Recherches sur le développement normal et pathologique du système immunitaire INSERM U429, Hôpital Necker-Enfants Malades, 75000 Paris, France d Department of Neurology and ‘Centre de référence neuropathies périphériques rares’, CHU Dupuytrens, 87000 Limoges, France b
a r t i c l e
i n f o
Article history: Received 14 March 2014 Received in revised form 30 May 2014 Accepted 13 June 2014 Available online 21 June 2014 Keywords: Chediak–Higashi syndrome LYST Lipofuscin Motor neuropathy Motor neuron disorder Schwann cell
a b s t r a c t Chediak–Higashi syndrome is a rare autosomal recessive disease characterized by partial oculocutaneous albinism, recurrent pyogenic infections and the presence of giant granules in many cells such as leucocytes (hallmark of the disease). Neurological symptoms are rare. We describe two sisters who presented the same phenotype of slowly progressive motor neuronopathy (with Babinski sign in one patient); biopsy of the sural nerve showed an abnormal endoneurial accumulation of lipofuscin granules. We discuss these two observations and compare them with the few case reports of neuropathy in Chediak–Higashi syndrome. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Chediak–Higashi syndrome (CHS) (MIM #124500) is a rare recessive autosomal disorder characterized by severe immunologic defects in childhood, partial oculocutaneous albinism, bleeding diathesis and neurological symptoms [1]. The pathological hallmark is the presence of giant granules (including lysosomes) in granule-containing cells (commonly white blood cells). CHS is due to mutations of the LYST (lysosomal trafficking regulator) gene located on the long arm of chromosome 1. Neurological manifestations are variable, and can affect both central and peripheral nervous systems. We report the case of two sisters presenting a motor neuronopathy that revealed CHS. A neuromuscular biopsy was performed in one patient (See Fig. 1).
patient showed a moderate symmetric distal and proximal weakness of the lower limbs (MRC score of 4/5 on the psoas and the tibialis anterior muscles). Tendon reflexes were absent in the lower limbs and weak in the upper limbs. The patient had no sensory dysfunction, and no pyramidal or cerebellar signs. Brain and spine MRI were normal. Ancillary tests were normal, except for the presence of coarse giant peroxidasepositive granules in the cytoplasm of neutrophils in the blood, indicative of CHS. Development was normal during infancy, and she presented neither oculocutaneous albinism nor recurrent pyogenic infections. At age 47, she experienced increased weakness of the lower limbs (MRC = 3/5 on the psoas muscles and 4/5 on the tibialis anterior muscles), but no weakness in the upper limbs where there were profuse fasciculations and no pyramidal signs.
2. Patients 2.2. Case 2 2.1. Case 1 A 34 year-old woman developed a progressive distal weakness of the lower limbs causing right recurrent ankle sprains then frequent falls. She also complained of ‘heavy legs’ and frequent calf cramps. Three months after the onset of symptoms, clinical examination of the
⁎ Corresponding author. E-mail address: [email protected] (J.-M. Vallat).
http://dx.doi.org/10.1016/j.jns.2014.06.026 0022-510X/© 2014 Elsevier B.V. All rights reserved.
The sister of patient 1 also presented a pure motor weakness of the lower limbs during childhood, with a slowly progressive course. At age 41, the MRC score was 3/5 on the proximal and 4/5 on the distal muscles of the lower limbs (no motor deficit of the upper limbs). She also presented fasciculations on the tongue. Tendon reflexes were absent in the lower limbs and weak in the upper limbs. A bilateral Babinski sign was present. Brain and spine MRI was normal. In common with her sister, she had no past history of oculocutaneous albinism or recurrent pyogenic infection.
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S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
3. Results 3.1. Electrophysiological studies They showed normal motor and sensory nerve conduction velocities in the upper and lower limbs of both sisters (Tables 1 and 2); in case 1, the motor amplitude was mildly decreased in the four limbs, but was normal in case 2 (normal values are presented in the tables). Needle electromyography showed a reduced recruitment pattern of the motor units (with an increase in duration and amplitude) and a partial denervation in the four limbs in the two sisters (and in the tongue in case 2). In both sisters, we observed a few fibrillation potentials in all studied muscles. 3.2. Genetic analysis For both sisters, we found compound heterozygous mutations in the LYST gene, c.9488ANG (p.Y3163C) and c.10424CNT (p.S3475F), whereas their mother only harbored the c.10424CNT mutation. 3.3. Pathological study Superficial peroneal nerve and peroneal brevis muscle biopsies were only carried out in case 1 (Fig. 1). No abnormality was observed on light microscopy, either on paraffin and Epon semi thin sections. No significant lesion was observed on the nerve by electron microscopy, except for the presence of numerous lipofuscin granules in Schwann cells, axons, fibroblasts, endothelial cells and pericytes of endoneural capillaries. The density of lipofuscin granules was 6 for 1000 nerve fibers (unmyelinated and myelinated) in case 1, but it was only 1.5 for 1000 in a normal control subject of the same age. Inflammatory infiltrates were not seen. There was severe neurogenic muscular atrophy on muscle biopsy; by electron microscopy we did not evidence any increase in lipofuscin granules.
Fig. 1. A — semi-thin transverse section. Toluidine blue. Superficial peroneal nerve. There is no lesion of the nerve fibers and of the interstitial tissue. B — electron microscopy. Transverse section. Presence of a typical lipofuscin granule in the cytoplasm of an unmyelinated Schwann cell. Note the characteristic electron-dense content and the lipid droplets; this aspect was the most frequently observed.
4. Discussion Neurological dysfunctions are usually late-onset manifestations of CHS and include cognitive impairment, autonomic dysfunction, parkinsonism, ataxia, seizures, spasticity, movement disorders, neuropathies and cranial nerve palsies [2]. To date, only a few cases of peripheral nervous system involvement have been reported: we have found only 13 patients (ours included) with peripheral nervous system involvement and CHS (Table 3): in the few reported cases, neurological symptoms precede the diagnosis of CHS in half of the patients (7/13), as in
Table 1 Motor conduction study of the two patients.
Case 1
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Case 2
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Nerve
Distal amplitude (mV)
Distal latency (ms)
Motor nerve conduction velocity (m/s)
F wave latency (ms)
Conduction block
Median Ulnar Common peroneal Tibial nerve Median Ulnar Common peroneal Tibial nerve Median Ulnar Common peroneal Tibial nerve Median Ulnar Common peroneal Tibial nerve
ND 5.7 1.9 5.7 6.4 ND 2.2 7.4 9.5 7.2 4.5 3.5 12.4 5.4 4.8 4.2
ND 2.7 4.6 5.8 3.7 ND 4.2 4.4 3.44 1.99 5 6.4 2.52 1.86 4.68 4.85
ND 54.8 45.7 52.8 58 ND 42.9 43.5 47.8 58.2 48.2 ND 51.6 51.6 46.3 43.1
ND 27.8 49 50.6 27 ND 48.6 ND 23 23.6 ND 40.4 22.8 23.5 42.4 46.4
ND No No No No ND No No No No ND No No No No No
ND = no data. Normal values of our laboratory: median nerve (Amp N 6 mV; DL b 3.7 ms; NCV N 48 m/s), ulnar nerve (Amp N 6 mV; DL b 3.2 ms; NCV N 50 m/s), common peroneal nerve (Amp N 3 mV; DL b 5 ms; NCV N 42 m/s), and tibial nerve (Amp N 6 mV; DL b 5.5 ms; NCV N 42 m/s).
S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
205
Table 2 Sensory conduction study of the two patients.
Case 1
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Case 2
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Median Ulnar Peroneal Sural Median Ulnar Peroneal Sural Median Ulnar Peroneal Sural Median Ulnar Peroneal Sural
Distal amplitude (μV)
Nerve conduction velocity (m/s)
20 ND ND 5.7 ND 6.6 1.8 6.2 23.2 23.9 7.9 12.8 40.3 8.6 12.8 20
56.5 ND ND 48 ND 60 50 46.4 55.1 61.5 41.1 47.4 64.5 64.9 47.4 42.3
NCV = nerve conduction velocity; ND = no data. Normal values of our laboratory: median nerve (Amp N 10 μV on index; NCV N 45 m/s), ulnar nerve (Amp N 8 μV; NCV N 45 m/s), peroneal nerve (Amp N 5 μV; NCV N 40 m/s), tibial nerve (Amp N 10 μV; NCV N 42 m/s).
our two patients; it may be sensorimotor and axonal with loss of large myelinated fibers and unmyelinated axons [3,4]. In our patients, we observed a motor neuropathy mimicking an anterior horn involvement (with no microscopical lesion of a biopsied sensory nerve) as has also been described in a few other reports [5,6]. Rarely, autopsy has revealed axonal lesions and large endoneurial lymphohistiocytic infiltrates as in case 1 of Kritzler et al. [7] and case 2 of Sung et al. [8]. In case 2 of Sung et al., such patchy lesions had been missed by a nerve biopsy [8,9]. The neuropathological hallmark of CHS could be cytoplasmic inclusions (lipofuscin granules) in various endoneurial cells as we observed here, and was also described by Blume & Wolff (case 4) in Schwann cells, endoneurial macrophages, fibroblasts, endothelial cells and pericytes [5]; these lipofuscin deposits have been described in various types of neurons at autopsy as well [3,4,8]. Lipofuscin is a reliable marker of aging, observed in post-mitotic and long-lived cells. These accumulations (composed of degraded proteins and a variety of lipid-like materials derived from the oxidation of polyunsaturated fatty acids) have been observed in the brain of agerelated neurodegenerative diseases [10]. With age, an accumulation of polyubiquitinated and oxidatively damaged proteins (which distend lysosomes overwhelmed with lipofuscin) is observed within nerves [11]. The LYST gene (CHS1) encodes a cytoplasmic protein that modulates lysosomal exocytosis and interacts with other cytoplasmic proteins (14-3-3 protein, calmodulin, …) playing a role in the regulation of vesicular transport or signal transduction [12]. Mutations of LYST disrupt the size and function of lysosomes that are unable to degrade auto- and hetero-phagocytosed substances, leading to the formation of lipofuscin. In our case, and also in the observation of Blume & Wolff [5], the abnormal increase of lipofuscin granules did not induce sensory nerve lesions. Nevertheless, some pathologies are associated with early age-independent deposition of lipofuscin pigments (‘ceroid’) pharmacologically induced or due to genetic deficiency of lysosomal enzymes (lipofuscinoses) [10]. Our case shows that peripheral nervous involvement may reveal CHS. At the present time, it seems that the nerve lesions are heterogeneous, but that lipofuscin granules may be detected in numerous nerve cell
types without any clinical manifestations. Except in neuronal ceroidlipofuscinoses [13], such storage has never been described in children or young adults, so these abnormalities may be a marker of CHS. Conflict of interest None of the authors have financial or other relationships that might lead to a perceived conflict of interest. References [1] Kaplan J, De Domenico I, Ward DM. Chediak–Higashi syndrome. Curr Opin Hematol 2008;15:22–9. [2] Introne W, Boissy RE, Gahl WA. Clinical, molecular and biological aspects of Chediak–Higashi syndrome. Mol Genet Metab 1999;68:283–303. [3] Misra VP, King RH, Harding AE, Muddle JR, Thomas PK. Peripheral neuropathy in the Chediak–Higashi syndrome. Acta Neuropathol 1991;81:354–8. [4] Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak–Higashi syndrome. Blood 2005;106:40–2. [5] Blume RS, Wolff SM. The Chediak–Higashi syndrome: studies in four patients and a review of the literature. Medicine 1972;51:247–80. [6] Weisfeld-Adams JD, Mehta L, Rucker JC, Dembitzer FR, Szporn A, Lublin FD, et al. Atypical Chediak–Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease. Orphanet J Rare Dis 2013;8. [7] Kritzler RA, Terner JY, Lindenbaum J, Magidson J, Williams R, Presig R, et al. Chediak– Higashi syndrome. Cytologic and serum lipid observations in a case and family. Am J Med 1964;36:583-94. [8] Sung JH, Meyers JP, Stadlan EM, Cowen D, Wolf A. Neuropathological changes in Chediak–Higashi disease. J Neuropathol Exp Neurol 1969;28:86–118. [9] Lockman LA, Kennedy WR, White JG. The Chediak–Higashi syndrome: electrophysiological and electron microscopic observations on the peripheral neuropathy. J Pediatr 1967;70:942–51. [10] Terman A, Brunk UT. Lipofuscin. Int J Biochem Cell Biol 2004;36:1400–4. [11] Opalach K, Rangaraju S, Madorsky I, Leeuwenburgh C, Notterpek L. Lifelong calorie restriction alleviates age-related oxidative damage in peripheral nerves. Rejunevation Res 2010;13:65–74. [12] Nagai K, Ochi F, Terui K, Maeda M, Ohga S, Kanegane H, et al. Clinical characteristics and outcomes of Chediak–Higashi syndrome: a nationwide survey in Japan. Pediatr Blood Cancer 2013;60:1582–6. [13] Jadav RH, Sinha S, Yasha TC, Aravinda H, Gayathri N, Rao S, et al. Clinical, electrophysiological, imaging, and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses (NCL) and its subtypes. Pediatr Neurol 2013;50:85–95.
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Table 3 Summary of the observations of neuropathy in Chediak–Higashi syndrome. Patient
LYST mutation
Age at diagnosis of CHS
Age at onset of neurological troubles
Neurological signs (clinical/radiological)
Electrophysiological study
Age at nerve biopsy
Other associated disease
- Moderate distal and proximal weakness in the lower limbs - Deep tendon reflexes were absent in the lower limbs and reduced in the upper limbs - Profuse fasciculations in the upper limbs - No sensory, pyramidal or cerebellar symptoms; no parkinsonism - Brain and spine MRI were normal - Moderate distal and proximal weakness of the lower limbs - Deep tendon reflexes were absent in the lower limbs and reduced in the upper limbs - Pyramidal signs (bilateral Babinski sign), but no sensory or cerebellar symptoms; no parkinsonism - Brain and spine MRI were normal - Paraplegia and spasticity (wheelchair-bound) - Cerebellar ataxia - Parkinsonism (no improvement with levodopa-carbidopa) - Reduced deep tendon reflexes in the lower limbs - Mild dementia syndrome - Brain MRI showed global atrophy and T2/FLAIR signal intensity in periventricular white matter - Cerebellar ataxia - Leg weakness - Parkinsonism (subjective benefit with levodopa–carbidopa) - Cognitive impairment - Reduced deep tendon reflexes in the four limbs - Brain MRI showed mild global atrophy and mild cerebellar volume loss - Brisk reflexes int lower limbs - Weakness in lower extremities - Upper extremity tremor and parkinsonism (the patient did not tolerate levodopa–carbidopa) - Brain MRI was normal
- Normal motor and sensory nerve conduction velocities - Mild decrease of CMAP amplitude in the four limbs reduced recruitment pattern of the motor units (with an increase in duration and amplitude) and a partial denervation in the four limbs
34 years
–
- Normal motor and sensory nerve conduction velocities reduced recruitment pattern of the motor units (with an increase in duration and amplitude) and a partial denervation in the four limbs and in the tongue
No biopsy –
Our observations Patient 1
c.9488ANG (p.Y3163C) and 34 years c.10424CNT (p.S3475F)
34 years
Patient 2
c.9488ANG (p.Y3163C) and 41 years c.10424CNT (p.S3475F)
Childhood
III.9
c.9827_9832ATACAA (p.Asn3276_Thr3277del)
40 years
31 years
III.12 (brother 1) c.9827_9832ATACAA (p.Asn3276_Thr3277del)
38 years
Early in the fourth decade
III.14 (brother 2) c.9827_9832ATACAA (p.Asn3276_Thr3277del)
33 years
29 years
Patient 1
2.5 years
22 years
Weisfeld-Adams et al. (2013)
c.3310CNT (p.Arg1104)
No biopsy – - Reduced amplitudes with normal conduction velocities (and normal left peroneal nerve F waves) - Subacute axonal neuropathy (more severe in the lower limbs)
- Motor neuropathy
No biopsy –
- Polyradiculopathy
No biopsy Radiculopathy secondary to spinal arteriovenous malformation (age was 28) 27 years
- Axonal sensorimotor neuropathy
S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
Reference
Tardieu et al. (2005)
Misra et al. (1994)
Patient 2
–
Patient 3
–
Case 1
–
Pettit and Berdal (1984)
–
–
Lockman et al. (1967)
–
–
Kriztler et al. (1964)
–
–
Type 2 diabetes (since age of 20) - Axonal sensorimotor neuropathy
20 years
No
- Axonal sensory neuropathy
28 years
No
- Only the right sural nerve sensory action potential was absent - Somatosensory evoked potentials were normal - Central motor conduction was delayed on the left abductor digiti minimi (12.7 ms)
33 years
No
No
No biopsy No
- Mild slowing on the peroneal and posterior tibial conduction velocities
No biopsy No
- Decrease of nerve conduction velocities in the four limbs; no motor potential in the lower limbs
11 years
No
No
16 years (autopsy)
No
S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
Case 2
- Cerebellar ataxia - Proximal weakness of the four limbs - Generalized areflexia 15 months 20 years - Cerebellar ataxia - Distal weakness of lower and upper limbs - Marked distal sensory loss of the lower limbs - Pes cavus - Generalized areflexia 5 years 24 years - Cerebellar ataxia - Tremor/myoclonus - Nystagmus - Generalized areflexia 9 years 29 years - Generalized tonico–clonic seizures - Dysarthria - Generalized areflexia - Mild distal loss of vibrations in the lower limbs - Mild upper limbs ataxia (with postural tremor) - Bilateral extensor plantar responses 5 years 29 years - Generalized areflexia - Mild upper limbs ataxia - Slight reduction of position and vibration sense and pain appreciation to midcalf and the wrists - Mild proprioceptive ataxia 25 years 19 years - Balance difficulty - Intention tremor - Absent deep tendon reflexes in the lower limbs (weak in the upper limbs) 11 years 9 years - Severe weakness of the lower limbs and moderate weakness in the upper limbs (including the shoulder girdles) - Reduced deep tendon reflexes (knees and ankles) - No sensory trouble 16 years 16 years (8 weeks - Right Bell's palsy after diagnosis) - Paresthesias of the soles of the feet - Loss of deep tendon reflexes - Bilateral foot drop
207
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Motor neuronopathy in Chediak–Higashi syndrome S. Mathis a, P. Cintas b, G. de Saint-Basile c, L. Magy d, B. Funalot d, J.-M. Vallat d,⁎ a
Department of Neurology, CHU Poitiers, University of Poitiers, 2 rue de la Milétrie, 86021 Poitiers, France Department of Neurology, CHU Rangueil, 1 avenue J. Poulhès, 31059 Toulouse, France c Unité de Recherches sur le développement normal et pathologique du système immunitaire INSERM U429, Hôpital Necker-Enfants Malades, 75000 Paris, France d Department of Neurology and ‘Centre de référence neuropathies périphériques rares’, CHU Dupuytrens, 87000 Limoges, France b
a r t i c l e
i n f o
Article history: Received 14 March 2014 Received in revised form 30 May 2014 Accepted 13 June 2014 Available online 21 June 2014 Keywords: Chediak–Higashi syndrome LYST Lipofuscin Motor neuropathy Motor neuron disorder Schwann cell
a b s t r a c t Chediak–Higashi syndrome is a rare autosomal recessive disease characterized by partial oculocutaneous albinism, recurrent pyogenic infections and the presence of giant granules in many cells such as leucocytes (hallmark of the disease). Neurological symptoms are rare. We describe two sisters who presented the same phenotype of slowly progressive motor neuronopathy (with Babinski sign in one patient); biopsy of the sural nerve showed an abnormal endoneurial accumulation of lipofuscin granules. We discuss these two observations and compare them with the few case reports of neuropathy in Chediak–Higashi syndrome. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Chediak–Higashi syndrome (CHS) (MIM #124500) is a rare recessive autosomal disorder characterized by severe immunologic defects in childhood, partial oculocutaneous albinism, bleeding diathesis and neurological symptoms [1]. The pathological hallmark is the presence of giant granules (including lysosomes) in granule-containing cells (commonly white blood cells). CHS is due to mutations of the LYST (lysosomal trafficking regulator) gene located on the long arm of chromosome 1. Neurological manifestations are variable, and can affect both central and peripheral nervous systems. We report the case of two sisters presenting a motor neuronopathy that revealed CHS. A neuromuscular biopsy was performed in one patient (See Fig. 1).
patient showed a moderate symmetric distal and proximal weakness of the lower limbs (MRC score of 4/5 on the psoas and the tibialis anterior muscles). Tendon reflexes were absent in the lower limbs and weak in the upper limbs. The patient had no sensory dysfunction, and no pyramidal or cerebellar signs. Brain and spine MRI were normal. Ancillary tests were normal, except for the presence of coarse giant peroxidasepositive granules in the cytoplasm of neutrophils in the blood, indicative of CHS. Development was normal during infancy, and she presented neither oculocutaneous albinism nor recurrent pyogenic infections. At age 47, she experienced increased weakness of the lower limbs (MRC = 3/5 on the psoas muscles and 4/5 on the tibialis anterior muscles), but no weakness in the upper limbs where there were profuse fasciculations and no pyramidal signs.
2. Patients 2.2. Case 2 2.1. Case 1 A 34 year-old woman developed a progressive distal weakness of the lower limbs causing right recurrent ankle sprains then frequent falls. She also complained of ‘heavy legs’ and frequent calf cramps. Three months after the onset of symptoms, clinical examination of the
⁎ Corresponding author. E-mail address: [email protected] (J.-M. Vallat).
http://dx.doi.org/10.1016/j.jns.2014.06.026 0022-510X/© 2014 Elsevier B.V. All rights reserved.
The sister of patient 1 also presented a pure motor weakness of the lower limbs during childhood, with a slowly progressive course. At age 41, the MRC score was 3/5 on the proximal and 4/5 on the distal muscles of the lower limbs (no motor deficit of the upper limbs). She also presented fasciculations on the tongue. Tendon reflexes were absent in the lower limbs and weak in the upper limbs. A bilateral Babinski sign was present. Brain and spine MRI was normal. In common with her sister, she had no past history of oculocutaneous albinism or recurrent pyogenic infection.
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S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
3. Results 3.1. Electrophysiological studies They showed normal motor and sensory nerve conduction velocities in the upper and lower limbs of both sisters (Tables 1 and 2); in case 1, the motor amplitude was mildly decreased in the four limbs, but was normal in case 2 (normal values are presented in the tables). Needle electromyography showed a reduced recruitment pattern of the motor units (with an increase in duration and amplitude) and a partial denervation in the four limbs in the two sisters (and in the tongue in case 2). In both sisters, we observed a few fibrillation potentials in all studied muscles. 3.2. Genetic analysis For both sisters, we found compound heterozygous mutations in the LYST gene, c.9488ANG (p.Y3163C) and c.10424CNT (p.S3475F), whereas their mother only harbored the c.10424CNT mutation. 3.3. Pathological study Superficial peroneal nerve and peroneal brevis muscle biopsies were only carried out in case 1 (Fig. 1). No abnormality was observed on light microscopy, either on paraffin and Epon semi thin sections. No significant lesion was observed on the nerve by electron microscopy, except for the presence of numerous lipofuscin granules in Schwann cells, axons, fibroblasts, endothelial cells and pericytes of endoneural capillaries. The density of lipofuscin granules was 6 for 1000 nerve fibers (unmyelinated and myelinated) in case 1, but it was only 1.5 for 1000 in a normal control subject of the same age. Inflammatory infiltrates were not seen. There was severe neurogenic muscular atrophy on muscle biopsy; by electron microscopy we did not evidence any increase in lipofuscin granules.
Fig. 1. A — semi-thin transverse section. Toluidine blue. Superficial peroneal nerve. There is no lesion of the nerve fibers and of the interstitial tissue. B — electron microscopy. Transverse section. Presence of a typical lipofuscin granule in the cytoplasm of an unmyelinated Schwann cell. Note the characteristic electron-dense content and the lipid droplets; this aspect was the most frequently observed.
4. Discussion Neurological dysfunctions are usually late-onset manifestations of CHS and include cognitive impairment, autonomic dysfunction, parkinsonism, ataxia, seizures, spasticity, movement disorders, neuropathies and cranial nerve palsies [2]. To date, only a few cases of peripheral nervous system involvement have been reported: we have found only 13 patients (ours included) with peripheral nervous system involvement and CHS (Table 3): in the few reported cases, neurological symptoms precede the diagnosis of CHS in half of the patients (7/13), as in
Table 1 Motor conduction study of the two patients.
Case 1
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Case 2
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Nerve
Distal amplitude (mV)
Distal latency (ms)
Motor nerve conduction velocity (m/s)
F wave latency (ms)
Conduction block
Median Ulnar Common peroneal Tibial nerve Median Ulnar Common peroneal Tibial nerve Median Ulnar Common peroneal Tibial nerve Median Ulnar Common peroneal Tibial nerve
ND 5.7 1.9 5.7 6.4 ND 2.2 7.4 9.5 7.2 4.5 3.5 12.4 5.4 4.8 4.2
ND 2.7 4.6 5.8 3.7 ND 4.2 4.4 3.44 1.99 5 6.4 2.52 1.86 4.68 4.85
ND 54.8 45.7 52.8 58 ND 42.9 43.5 47.8 58.2 48.2 ND 51.6 51.6 46.3 43.1
ND 27.8 49 50.6 27 ND 48.6 ND 23 23.6 ND 40.4 22.8 23.5 42.4 46.4
ND No No No No ND No No No No ND No No No No No
ND = no data. Normal values of our laboratory: median nerve (Amp N 6 mV; DL b 3.7 ms; NCV N 48 m/s), ulnar nerve (Amp N 6 mV; DL b 3.2 ms; NCV N 50 m/s), common peroneal nerve (Amp N 3 mV; DL b 5 ms; NCV N 42 m/s), and tibial nerve (Amp N 6 mV; DL b 5.5 ms; NCV N 42 m/s).
S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
205
Table 2 Sensory conduction study of the two patients.
Case 1
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Case 2
Right
Upper limbs Lower limbs
Left
Upper limbs Lower limbs
Median Ulnar Peroneal Sural Median Ulnar Peroneal Sural Median Ulnar Peroneal Sural Median Ulnar Peroneal Sural
Distal amplitude (μV)
Nerve conduction velocity (m/s)
20 ND ND 5.7 ND 6.6 1.8 6.2 23.2 23.9 7.9 12.8 40.3 8.6 12.8 20
56.5 ND ND 48 ND 60 50 46.4 55.1 61.5 41.1 47.4 64.5 64.9 47.4 42.3
NCV = nerve conduction velocity; ND = no data. Normal values of our laboratory: median nerve (Amp N 10 μV on index; NCV N 45 m/s), ulnar nerve (Amp N 8 μV; NCV N 45 m/s), peroneal nerve (Amp N 5 μV; NCV N 40 m/s), tibial nerve (Amp N 10 μV; NCV N 42 m/s).
our two patients; it may be sensorimotor and axonal with loss of large myelinated fibers and unmyelinated axons [3,4]. In our patients, we observed a motor neuropathy mimicking an anterior horn involvement (with no microscopical lesion of a biopsied sensory nerve) as has also been described in a few other reports [5,6]. Rarely, autopsy has revealed axonal lesions and large endoneurial lymphohistiocytic infiltrates as in case 1 of Kritzler et al. [7] and case 2 of Sung et al. [8]. In case 2 of Sung et al., such patchy lesions had been missed by a nerve biopsy [8,9]. The neuropathological hallmark of CHS could be cytoplasmic inclusions (lipofuscin granules) in various endoneurial cells as we observed here, and was also described by Blume & Wolff (case 4) in Schwann cells, endoneurial macrophages, fibroblasts, endothelial cells and pericytes [5]; these lipofuscin deposits have been described in various types of neurons at autopsy as well [3,4,8]. Lipofuscin is a reliable marker of aging, observed in post-mitotic and long-lived cells. These accumulations (composed of degraded proteins and a variety of lipid-like materials derived from the oxidation of polyunsaturated fatty acids) have been observed in the brain of agerelated neurodegenerative diseases [10]. With age, an accumulation of polyubiquitinated and oxidatively damaged proteins (which distend lysosomes overwhelmed with lipofuscin) is observed within nerves [11]. The LYST gene (CHS1) encodes a cytoplasmic protein that modulates lysosomal exocytosis and interacts with other cytoplasmic proteins (14-3-3 protein, calmodulin, …) playing a role in the regulation of vesicular transport or signal transduction [12]. Mutations of LYST disrupt the size and function of lysosomes that are unable to degrade auto- and hetero-phagocytosed substances, leading to the formation of lipofuscin. In our case, and also in the observation of Blume & Wolff [5], the abnormal increase of lipofuscin granules did not induce sensory nerve lesions. Nevertheless, some pathologies are associated with early age-independent deposition of lipofuscin pigments (‘ceroid’) pharmacologically induced or due to genetic deficiency of lysosomal enzymes (lipofuscinoses) [10]. Our case shows that peripheral nervous involvement may reveal CHS. At the present time, it seems that the nerve lesions are heterogeneous, but that lipofuscin granules may be detected in numerous nerve cell
types without any clinical manifestations. Except in neuronal ceroidlipofuscinoses [13], such storage has never been described in children or young adults, so these abnormalities may be a marker of CHS. Conflict of interest None of the authors have financial or other relationships that might lead to a perceived conflict of interest. References [1] Kaplan J, De Domenico I, Ward DM. Chediak–Higashi syndrome. Curr Opin Hematol 2008;15:22–9. [2] Introne W, Boissy RE, Gahl WA. Clinical, molecular and biological aspects of Chediak–Higashi syndrome. Mol Genet Metab 1999;68:283–303. [3] Misra VP, King RH, Harding AE, Muddle JR, Thomas PK. Peripheral neuropathy in the Chediak–Higashi syndrome. Acta Neuropathol 1991;81:354–8. [4] Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak–Higashi syndrome. Blood 2005;106:40–2. [5] Blume RS, Wolff SM. The Chediak–Higashi syndrome: studies in four patients and a review of the literature. Medicine 1972;51:247–80. [6] Weisfeld-Adams JD, Mehta L, Rucker JC, Dembitzer FR, Szporn A, Lublin FD, et al. Atypical Chediak–Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease. Orphanet J Rare Dis 2013;8. [7] Kritzler RA, Terner JY, Lindenbaum J, Magidson J, Williams R, Presig R, et al. Chediak– Higashi syndrome. Cytologic and serum lipid observations in a case and family. Am J Med 1964;36:583-94. [8] Sung JH, Meyers JP, Stadlan EM, Cowen D, Wolf A. Neuropathological changes in Chediak–Higashi disease. J Neuropathol Exp Neurol 1969;28:86–118. [9] Lockman LA, Kennedy WR, White JG. The Chediak–Higashi syndrome: electrophysiological and electron microscopic observations on the peripheral neuropathy. J Pediatr 1967;70:942–51. [10] Terman A, Brunk UT. Lipofuscin. Int J Biochem Cell Biol 2004;36:1400–4. [11] Opalach K, Rangaraju S, Madorsky I, Leeuwenburgh C, Notterpek L. Lifelong calorie restriction alleviates age-related oxidative damage in peripheral nerves. Rejunevation Res 2010;13:65–74. [12] Nagai K, Ochi F, Terui K, Maeda M, Ohga S, Kanegane H, et al. Clinical characteristics and outcomes of Chediak–Higashi syndrome: a nationwide survey in Japan. Pediatr Blood Cancer 2013;60:1582–6. [13] Jadav RH, Sinha S, Yasha TC, Aravinda H, Gayathri N, Rao S, et al. Clinical, electrophysiological, imaging, and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses (NCL) and its subtypes. Pediatr Neurol 2013;50:85–95.
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Table 3 Summary of the observations of neuropathy in Chediak–Higashi syndrome. Patient
LYST mutation
Age at diagnosis of CHS
Age at onset of neurological troubles
Neurological signs (clinical/radiological)
Electrophysiological study
Age at nerve biopsy
Other associated disease
- Moderate distal and proximal weakness in the lower limbs - Deep tendon reflexes were absent in the lower limbs and reduced in the upper limbs - Profuse fasciculations in the upper limbs - No sensory, pyramidal or cerebellar symptoms; no parkinsonism - Brain and spine MRI were normal - Moderate distal and proximal weakness of the lower limbs - Deep tendon reflexes were absent in the lower limbs and reduced in the upper limbs - Pyramidal signs (bilateral Babinski sign), but no sensory or cerebellar symptoms; no parkinsonism - Brain and spine MRI were normal - Paraplegia and spasticity (wheelchair-bound) - Cerebellar ataxia - Parkinsonism (no improvement with levodopa-carbidopa) - Reduced deep tendon reflexes in the lower limbs - Mild dementia syndrome - Brain MRI showed global atrophy and T2/FLAIR signal intensity in periventricular white matter - Cerebellar ataxia - Leg weakness - Parkinsonism (subjective benefit with levodopa–carbidopa) - Cognitive impairment - Reduced deep tendon reflexes in the four limbs - Brain MRI showed mild global atrophy and mild cerebellar volume loss - Brisk reflexes int lower limbs - Weakness in lower extremities - Upper extremity tremor and parkinsonism (the patient did not tolerate levodopa–carbidopa) - Brain MRI was normal
- Normal motor and sensory nerve conduction velocities - Mild decrease of CMAP amplitude in the four limbs reduced recruitment pattern of the motor units (with an increase in duration and amplitude) and a partial denervation in the four limbs
34 years
–
- Normal motor and sensory nerve conduction velocities reduced recruitment pattern of the motor units (with an increase in duration and amplitude) and a partial denervation in the four limbs and in the tongue
No biopsy –
Our observations Patient 1
c.9488ANG (p.Y3163C) and 34 years c.10424CNT (p.S3475F)
34 years
Patient 2
c.9488ANG (p.Y3163C) and 41 years c.10424CNT (p.S3475F)
Childhood
III.9
c.9827_9832ATACAA (p.Asn3276_Thr3277del)
40 years
31 years
III.12 (brother 1) c.9827_9832ATACAA (p.Asn3276_Thr3277del)
38 years
Early in the fourth decade
III.14 (brother 2) c.9827_9832ATACAA (p.Asn3276_Thr3277del)
33 years
29 years
Patient 1
2.5 years
22 years
Weisfeld-Adams et al. (2013)
c.3310CNT (p.Arg1104)
No biopsy – - Reduced amplitudes with normal conduction velocities (and normal left peroneal nerve F waves) - Subacute axonal neuropathy (more severe in the lower limbs)
- Motor neuropathy
No biopsy –
- Polyradiculopathy
No biopsy Radiculopathy secondary to spinal arteriovenous malformation (age was 28) 27 years
- Axonal sensorimotor neuropathy
S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
Reference
Tardieu et al. (2005)
Misra et al. (1994)
Patient 2
–
Patient 3
–
Case 1
–
Pettit and Berdal (1984)
–
–
Lockman et al. (1967)
–
–
Kriztler et al. (1964)
–
–
Type 2 diabetes (since age of 20) - Axonal sensorimotor neuropathy
20 years
No
- Axonal sensory neuropathy
28 years
No
- Only the right sural nerve sensory action potential was absent - Somatosensory evoked potentials were normal - Central motor conduction was delayed on the left abductor digiti minimi (12.7 ms)
33 years
No
No
No biopsy No
- Mild slowing on the peroneal and posterior tibial conduction velocities
No biopsy No
- Decrease of nerve conduction velocities in the four limbs; no motor potential in the lower limbs
11 years
No
No
16 years (autopsy)
No
S. Mathis et al. / Journal of the Neurological Sciences 344 (2014) 203–207
Case 2
- Cerebellar ataxia - Proximal weakness of the four limbs - Generalized areflexia 15 months 20 years - Cerebellar ataxia - Distal weakness of lower and upper limbs - Marked distal sensory loss of the lower limbs - Pes cavus - Generalized areflexia 5 years 24 years - Cerebellar ataxia - Tremor/myoclonus - Nystagmus - Generalized areflexia 9 years 29 years - Generalized tonico–clonic seizures - Dysarthria - Generalized areflexia - Mild distal loss of vibrations in the lower limbs - Mild upper limbs ataxia (with postural tremor) - Bilateral extensor plantar responses 5 years 29 years - Generalized areflexia - Mild upper limbs ataxia - Slight reduction of position and vibration sense and pain appreciation to midcalf and the wrists - Mild proprioceptive ataxia 25 years 19 years - Balance difficulty - Intention tremor - Absent deep tendon reflexes in the lower limbs (weak in the upper limbs) 11 years 9 years - Severe weakness of the lower limbs and moderate weakness in the upper limbs (including the shoulder girdles) - Reduced deep tendon reflexes (knees and ankles) - No sensory trouble 16 years 16 years (8 weeks - Right Bell's palsy after diagnosis) - Paresthesias of the soles of the feet - Loss of deep tendon reflexes - Bilateral foot drop
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