Selective type II muscle fiber hypertrophy in severe infantile spinal muscular atrophy

The diagnostic muscle biopsy finding in severe infantile spinal muscular atrophy (Werdnig-Hoffmann disease, SMA type 1) is considered to be large-group atrophy with isolated clusters of hypertrophic type I myofibers. We present a unique case of severe infantile spinal muscular atrophy with selective hypertrophy of type II myofibers. A male infant presented at age 2 months with breathing difficulties and by age 4 months was hypotonic and weak. Electromyography revealed denervation in all extremity muscles, and nerve conduction velocities were normal but with small compound muscle action potentials. Quadriceps muscle biopsy revealed many hypertrophied type II myofibers (myofibers with a mean least diameter of 25.4 microns). In contrast, the largest type I myofibers were 20 microns in least diameter (mean diameter, 14.9 microns), and there was a normal-size population of type II fibers (mean diameter, 15.7 microns). In addition, sheets of atrophic type I and type II fibers averaged 2.0 microns in least diameter. Sural nerve biopsy was normal. Breathing difficulties progressed, with death ensuing at age 5 1/2 months. Autopsy revealed atrophy of ventral spinal roots with normal dorsal roots. There was loss of anterior horn cells, while remnant neurons were reduced in size. No other pathologic changes were identified. This case indicates that in severe infantile spinal muscular atrophy, relative sparing of the motor units with type II myofibers may occur.     

Reinnervation of dystrophic muscles

OBJECTIVE: To analyse the regenerating capability of the peripheral nerve fibers and the capability of the muscle fibers to accept the regenerating and new nerve sprouts in myotonic dystrophy (MD). MATERIAL AND METHODS: One male, aged 58 years, diagnosed of MD at the age of 30 years, suffered neuralgic amyotrophy in the right shoulder girdle 4 weeks before admission. Needle EMG and nerve conduction studies were performed on admission and 6, 12, and 18 months later. RESULTS: On admission there were atrophy and absence of voluntary contraction in deltoids, supra- and infraspinatus muscles. EMG showed abundant fibrillations, positive sharp waves and myotonic bursts in these muscles without voluntary activity, consistent with axonal neuropathy of both axillary and suprascapular nerves. The follow-up showed signs of reinnervation 6 months later and slight loss of long duration and high amplitude MUPs at 18 months of evolution, with good clinical recovery. This is compatible with chronic neurogenic atrophy, presumably as an expression of type grouping. CONCLUSIONS: The reinnervation capability of the nerve fibers and the capability of muscle fibers membrane to accept regenerating and new nerve sprout remain in MD. Myotonic bursts persist after total denervation.     

A case of Sj?gren-Larsson syndrome with peripheral nerve involvement

A case of Sj?gren-Larsson syndrome (SLS) with peripheral nerve involvement was described. A patient was a 37-year-old man with marked mental retardation who had ichthyosis since several months of age. He developed spastic gait at age 20 and noticed muscle weakness and atrophy in lower extremities at age 30. On examination, electromyogram showed neurogenic changes with polyphasic motor unit potentials of high amplitude and long duration, and motor and sensory conduction velocities were slightly decreased in lower extremities. Muscle biopsy specimens of the left quadriceps showed grouped atrophy and pyknotic nuclear clumps, suggestive of neurogenic changes. Left sural nerve biopsy showed decreased number of myelinated fibers. On electron microscopy, some myelinated fibers revealed proliferation of the organelles in axons with disruption of the myelin sheath, and glycogen granules in Schwann cell cytoplasm. Unmyelinated fibers showed no reduction in the density, but accompanied numerous collagen pockets and Schwann cell cytoplasmic processes arranged in many stacks, suggesting the presence of some degenerative changes. With the present findings at peripheral level and a review of the literature, we may assume that SLS has extensive disorders of the ectodermal tissues including the peripheral nerve as well as the skin and the central nervous system.     

An interesting case of Leigh-like syndrome

A 12-year-old female child with motor developmental delay presented with persistent vomiting, recurrent falls and unsteadiness in dark since 2 years of age. There was decline in scholastic performance, bulbar symptoms and aggravation of symptoms during intercurrent illness. Clinically, she had frontal and parietal lobar dysfunction, dysarthria, optic atrophy and LMN VII, IX, X, XII cranial nerve involvement. There was generalized hypotonia, distal muscle wasting, weakness, cerebellar signs and impaired vibration/position sense in distal extremities. Biochemical investigations revealed elevated serum/cerebrospinal fluid (CSF) lactate and CSF lactate pyruvate ratio. Neuroimaging demonstrated bilateral symmetrical T2 hyperintensities in basal ganglia, subcortical white matter, cerebellar hemispheres and posterior aspect of spinal cord. As certain atypical features like bilateral symmetrical T2 hyperintensities in subcortical white matter were also seen, metachromatic leukodystrophy was considered in differential diagnosis but ruled out by nerve biopsy. This case is reported for the presence of atypical neuroimaging features that are rarely found in Leigh''s disease.     

远端型遗传性运动神经病Ⅴ型一家系

目的 报道1个远端型遗传性运动神经病Ⅴ型(dHMN-Ⅴ)家系的临床、病理和基因改变特点.方法 该家系中连续4代有9例(4例男性,5例女性)在13～40岁之间发病,其中6例出现下肢无力;有2例女性患者仅出现双手肌肉无力和萎缩,其中1例出现锥体束征.先证者为20岁女性,13岁时发现双手肌肉萎缩和无力,15岁后出现下肢无力;肌电图提示神经源性损伤,神经传导速度检查显示运动神经复合肌肉动作电位波幅显著降低,伴随传导速度轻度减慢,感觉神经传导速度和动作电位波幅均正常.对先证者进行腓肠神经活体组织病理检查,并对先证者和其他4例发病者进行血Berardinelli-Seip先天性脂肪营养不良基因2(BSCL2)基因检查.结果 病理检查显示腓肠神经的有髓神经纤维数量轻度减少,伴随个别有髓神经纤维再生簇以及洋葱球样改变.基因检查显示BSCL2基因的第3号外显子存在263A→G杂合突变.结论 临床和基因检查证实该家系为dHMN-Ⅴ,其发病年龄和临床表现在同一家系中存在异质性,可以伴随轻微锥体束征和感觉神经损害.     

A case of chronic toluene poisoning with myopathic changes]

We reported a 27-year-old man, who had inhaled toluene vapor for 11 years and developed both polyneuropathy and myopathy. He gradually developed progressive muscular weakness in the limbs 2 months after the last inhalation and became nonambulant. Neurological examination revealed distal dominant muscular weakness and hypoactive deep tendon reflexes, especially in the legs. The cranial nerves were intact and neither sensory disturbances nor cerebellar signs were observed. Laboratory studies demonstrated mildly elevated serum CK value, but serum electrolytes and urinalysis were normal. Electromyogram showed a neurogenic pattern in the limbs and also a myogenic in the gastrocnemius muscle. Motor nerve conduction velocities were delayed in the limbs. The sural nerve biopsy specimens showed demyelination, myelin avoids, and axonal swelling compatible with toxic neuropathy. The muscle biopsy of the gastrocnemius revealed necrotic muscle fibers, vacuolated muscle fibers, phagocytosis, a disordered intermyofibrillary network, and small group atrophy on light microscopy. On electron microscopy, two outstanding findings were observed; the first, dilatation and proliferation of the membrane system, and the second, appearance of irregular membrano lamellar structures and vacuoles associated with abnormal membrane system. These histological findings suggest that toluene may affect directly the membrane system of muscle fibers and consequently induce rhabdomyolysis.     

A case of sensory ataxic neuropathy and polymyositis of perivascular type associated with Sj?gren's syndrome]

A 53-year old woman was admitted with of sensory disturbance and weakness of lower limbs which had progressed slowly in the previous ten years. A diagnosis of sensory ataxic neuropathy associated with Sj?gren's syndrome was made. A sural nerve biopsy showed marked loss of myelinated fibers. A muscle biopsy revealed atrophy of muscle fibers along with perivascular cellular infiltration. The dorsal root ganglia have been considered to be the main site affected in the ataxic neuropathy in Sj?gren's syndrome. However, the evidence for that was meager. The perivascular inflammatory change observed in the muscle may also have existed in the peripheral nervous system including the dorsal root ganglia.     

A case of Hoffmann's syndrome with peripheral neuropathy and various pathological findings in muscle biopsy

A 58-year-old hypothyroid man developed numbness in the extremities and muscular hypertrophy without pain. Needle electromyography was normal. Nerve conduction study revealed severe entrapment and impaired conduction velocity. Muscle biopsy demonstrated small group atrophy, scattered hypertrophic fibers, interstitial fibrosis and subsarcolemmal vaculoes. These vacuoles were stained dark with NADH-TR. On electron microscopy these vacuoles were filled with aggregated mitochondria and glycogen particles. These myopathological findings have been rarely described in Hoffmann's syndrome or Kocher-Debré-Semelaigne syndrome in the literature. Sural nerve biopsy revealed a loss of myelinated fibers in large diameter and relative increase in small diameter fibers. Teased fiber examination demonstrated segmental demyelination. The nerve biopsy findings indicate slowly progressive axonopathy. In Hoffmann's syndrome, associated peripheral neuropathy may play some role in the manifestation of clinical signs and symptoms including muscle weakness and some sensory disturbance.     

Congenital fiber type disproportion

Type I muscle fiber atrophy in childhood can be encountered in a variety of neuromuscular disorders. Congenital fiber type disproportion (CFTD) is one such condition which presents as a nonprogressive muscle weakness. The diagnosis is often made after excluding other differential diagnostic considerations. We present a 2-year-9-month-old full term boy who presented at 2 months with an inability to turn his head to the right. Over the next couple of years, he showed signs of muscle weakness, broad based gait and a positive Gower’s sign. He had normal levels of creatine kinase and normal electromyography. A biopsy of the vastus lateralis showed a marked variation in muscle fiber type. The adenosine triphosphate (ATP)-ase stains highlighted a marked type I muscle atrophy with rare scattered atrophic type II muscle fibers. No abnormalities were observed on the nicotinamide adenine dinucleotide (NADH), succinate dehydrogenase (SDH) or cytochrome oxidase stained sections. Ragged red fibers were not present on the trichrome stain. Abnormalities of glycogen or lipid deposition were not observed on the periodic acid–Schiff or Oil-Red-O stains. Immunostaining for muscular dystrophy associated proteins showed normal staining. Ultrastructural examination showed a normal arrangement of myofilaments, and a normal number and morphology for mitochondria. A diagnosis of CFTD was made after excluding other causes of type I atrophy including congenital myopathy. The lack of specific clinical and genetic disorder associated with CFTD suggests that it is a spectrum of a disease process and represents a diagnosis of exclusion.     

Familial bulbo-spinal muscular atrophy associated with testicular atrophy and sensory neuropathy (Kennedy-Alter-Sung syndrome). Autopsy case report of two brothers

Autopsy cases of two brothers with bulbo-spinal muscular atrophy associated with gynecomastia, testicular atrophy and sensory neuropathy are reported. The disease started with finger tremor, proximal muscle weakness and facial muscle twitching at the second and fourth decades, accompanied by bulbar signs and glove-stocking type sensory disturbance. Systemic neurogenic patterns and diminished sensory nerve action potential amplitudes were recorded by electrophysiological studies. A marked loss of myelinated fibers was noticed upon sural nerve biopsy. Gonadal hormone values were normal, except for elevated urinary estrogen. Postmortem examinations revealed a remarkable degeneration of the facial and hypoglossal nuclei, and the spinal cord motoneurons. The skeletal muscles and the tongue showed neurogenic muscular atrophy with fatty replacement. Testicular atrophy was prominent showing hyalinized seminiferous tubuli with nodular and diffuse Leydig cell hyperplasia, containing estrogen immunoreactive substance. These clinical and histological features seemed to be highly compatible with those of Kennedy-Alter-Sung type bulbo-spinal muscular atrophy. The involvement of sensory peripheral nerves, however, was a distinct feature of this family.     

Immune-mediated neuropathy and myopathy in post-streptococcal disease: electron-microscopical, morphometrical and immunohistochemical studies.

A 22-year-old man suffered from a complete flaccid tetraparesis and an immune complex-mediated rapid progressive glomerulonephritis after group A streptococcal infection. Serum creatine kinase was excessively elevated and myoglobinuria occurred. Nerve conduction studies revealed evidence of axonal neuropathy. Recovery was satisfactory within 18 months. Sural nerve and peroneus muscle biopsies were performed in the 4th and 14th week of the disease. Light microscopy of the sural nerve showed an incipient axonal type of neuropathy in the first biopsy. Ultrastructurally, Wallerian degeneration and endoneurial inflammatory cells were present. In the muscle biopsy, few atrophic fibers and altered blood vessels without further anomalies were found. In the second sural nerve biopsy, macrophages were numerous, some of which were immunoreactive for HLA-DR, and only a few myelinated and some unmyelinated nerve fibers remained. Muscle fibers in the second biopsy showed high-grade atrophy and myofibrillar abnormalities. Immunohistochemistry revealed diffuse endoneurial immunoglobulin deposition in the first sample, while in the later biopsy specimen, deposits of IgG, and kappa and lambda light chains were visible in circumscribed endoneurial areas. Immune-mediated neuropathy and myopathy are not well-known complications of streptococcal disease. This is, to our knowledge, the first detailed report on morphological findings in muscle and nerve in such a disorder.     

新生儿型神经轴索营养不良的皮肤神经和肌肉病理改变

目的　报道2例新生儿型神经轴索营养不良(INAD)的神经末梢和骨骼肌的病理改变特点。方法　2例患者均为男性,年龄分别为3岁及2岁,均于1岁左右出现智力和运动发育落后或倒退,头颅磁共振成像(MRI)均示小脑萎缩。肌电图提示骨骼肌神经源性损害。例1进行左侧腓肠神经、肌肉和皮肤活检,例2进行左小腿皮肤和肌肉活检,标本进行光镜和电镜检查。结果　2例患者皮下神经末梢均可见椭圆体状巨大轴索,其内充满空泡或致密物质。例1腓肠神经偶见小的致密轴索。例2的骨骼肌间小神经发现异常巨大轴索。两例骨骼肌均存在神经源性病理改变。电镜发现巨大轴索内存在颗粒样物质或空泡膜管样结构。结论　出现中枢神经系统、周围神经系统以及视神经的广泛受累提示INAD的可能性,而脑外病理检查发现神经末梢出现椭圆体样巨大轴索可以确诊该病。巨大轴索内的成分具有不同的超微结构特点。显著的皮肤神经末梢损害提示此病存在小纤维性周围神经病。     

A case of hereditary motor and sensory neuropathy of neuronal type with retardation of motor development

An atypical case of hereditary motor and sensory neuropathy of neuronal type with retardation of motor development was described. The patient was a 15-year-old boy who had suffered from distal muscle weakness with atrophy of four limbs and deformities of hands and feet since age 6 months. These symptoms were slowly progressive. He had never walked. His parents were not consanguinous. His parents and two siblings were unremarkable on neurological examination and on nerve conduction studies. On neurological examination, he showed severe degree of muscle weakness and atrophy in the distal upper and lower limbs, moderate degree of muscle weakness and atrophy in the proximal upper limbs and slight degree of made weakness and atrophy in the proximal upper limbs. Deep tendon reflexes in four limbs were decreased or absent. Vibration sensation was moderately decreased in the distal parts of four limbs. On the nerve conduction studies, no sensory nerve potential was recorded in the median, ulnar and sural nerves bilaterally. Motor nerve conduction velocity of the right tibial nerve was 21 m/sec and the amplitude of the compound muscle action potential (M-wave) was 0.15 mV, and no M-wave was elicited with the electrical stimulation of the median, ulnar and peroneal nerves. Neelde EMG showed fibrillation potentials and giant spikes with a reduction of the number of motor units. On sural nerve biopsy, the densities of both myelinated and unmyelinated fibers were severely decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral neuropathy detected on electrophysiological study as first manifestation of metachromatic leucodystrophy in infancy.

A case of infantile metachromatic leucodystrophy is described in which symptoms started at 1 year of age with weakness and hypotonus in the lower extremities. The electrophysiological status was typical of a polyneuropathy, showing fibrillation and a reduction of the nerve conduction velocity to 30 percent of the average for normal children of the same age. Clinical signs of a central lesion and mental regression were not evident until a year later. Nerve biopsy showed metachromatic granules in the phagocytes and in the Schwann cells, confirming the diagnosis of metachromatic leucodystrophy. In peripheral neuropathy in infancy without obvious cause, a nerve biopsy is the most appropriate method for diagnosis of the metachromatic leucodystrophy.     

The role of mitochondrial encephalopathies in progressive myoclonus epilepsy

The authors compare the clinical, neurophysiological and evolutive features of progressive myoclonus epilepsy (PME) associated with mitochondrial encephalomyopathy with ragged-red fibers (MERRF), based on 49 cases from the literature, and the two well-described types of degenerative PME: Baltic myoclonus (BM), of which over 100 cases have been reported from Finland, and Mediterranean myoclonus (MM), based on a personal series of 43 patients. Degenerative PMEs are age-dependent, recessively inherited conditions with homogeneous clinical signs and course; there are no major clinical symptoms beside the cardinal symptoms: generalized epileptic seizures, predominantly action myoclonus and cerebellar dysfunction; mental deterioration when present, is slight and progresses very slowly; associated neurological symptoms are uncommon and limited to mild spino-cerebellar involvement. In MERRF, the transmission is maternal, the age of onset is variable, the evolution is not stereotyped and associated symptoms are many (deafness, muscle weakness, optic atrophy, short stature, sensory disturbances, spasticity, clinical or neurophysiological signs of peripheral neuropathy, absence of motor reflexes); muscle biopsy generally shows ragged-red fibers. The differential diagnosis between these conditions is usually easy, although pathological examination (i.e. muscle biopsy) should be performed.     

An infant autopsy case of severe multicystic leukoencephalopathy

A boy aged 4 years and 2 months died of an unknown neurological disease, which had insidiously occurred around the age of one year. The case slowly developed sleeping tendency, spastic tetraplegia, optic nerve atrophy and flexion contracture but no epileptic seizures. There was neither consanguinity nor familial history of neurological disorders. The proband had intrauterine exposure to X-ray at the seventh fetal month. Laboratory examinations including antiviral antibodies and lysosomal enzymes provided no evidence for known brain disorders. Neuropathological examination revealed widespread multicystic destruction predominantly in the centrum semiovale. The subcortical arcuate fibers were spared. The commissural fibers as well as long tract fibers were also symmetrically affected. There was neither inflammatory reaction, calcification, Rosenthal fibers nor globoid cells. Axons were comparatively preserved. Tissue debris was not metachromatic in acid cresyl violet stain. Chemical analysis demonstrated no changes in fatty acid profiles. These clinicopathological features partly mimic leukoencephalopathy with vanishing white matter (van der Knaap), except for the lack of familial history and cerebellar signs, and the more extensive neuropathological lesions. Although the influence of intrauterine X-ray irradiation could not be neglected completely, reports of several similar cases in the literature suggests that this case had a new variant of child-onset multicystic leukoencephalopathy or leukodystrophy.     

Leber's disease with spastic paraplegia and peripheral neuropathy. Case report with nerve biopsy study

A 43-year-old patient with familial Leber's optic atrophy suffered from spastic paraplegia. Physical examination disclosed cerebellar and pyramidal signs and signs of peripheral neuropathy. On sural nerve biopsy, there were few large myelinated fibers, signs of axonal degeneration and thin myelin sheets. This case suggests an overlap syndrome with central and peripheral nervous system features of Leber's disease, spinocerebellar degeneration and peroneal muscular atrophy.     

Xeroderma pigmentosum: neurological, neurophysiological and morphological studies

In 3 cases of xeroderma pigmentosum showing signs of peripheral neuropathy, electrophysiological studies were made. In one of them, a sural nerve biopsy was performed. MCV obtained from the lower limbs were moderately reduced in all cases, and SCV could be obtained in only 1 case from the median nerve. Auditory brain stem responses were not obtainable in all cases. Sural nerve biopsy revealed a marked decrease of myelinated fibers and also suggested severe damage in both myelinated and unmyelinated fibers. Teased fiber study showed myelin ovoids and indicated axonal degeneration. Sensory nerves including the acoustic nerve may suffer damage earlier than the motor nerve. In all cases CT scans revealed brain atrophy and thickening of the skull.     

A case of acute quadriplegic myopathy]

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.     

胼胝体、锥体束和周围神经变性一家系报告

目的：报道一个以胼胝体、锥体束和周围神经变性为主要表现特点的隐性遗传性家族,探讨与其他复合型遗传性痉挛性截瘫的关系。方法：家族中姐弟二人发病,临床表现及脑电图,肌电图符合此病特点,对病人进行头颅MRI检查,并对先证者（弟弟）进行神经和肌肉活检,结果：MRI检查显示胼胝体发育不育,大脑和小脑轻度萎缩以及脑室系统扩大。肌肉活检显示肌纤维出现肥大和萎缩,萎缩肌纤维成组分布,神经活检显示小有髓神经纤维变性和再生簇形成。结论：我们发现的这个家系可能与日本人报道的隐性遗传痉挛性截瘫伴智能发育倒退、胼胝体发育和周围神经病属于同一类疾病,轴索性周围神经病是此病的一个常见病理改变。