Identification of de novo BSCL2 Ser90Leu mutation in a Korean family with Silver syndrome and distal hereditary motor neuropathy

Mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been identified in families with distal hereditary motor neuropathy (dHMN) and in families with SPG17-linked Silver syndrome. We studied the first Korean families with clinical features resembling classic Silver syndrome and dHMN type V. Direct sequencing analysis of the BSCL2 gene revealed a Ser90Leu mutation in the proband, a younger sister, and one of two sons of the proband. The clinical patterns in this family include presentation with lower-limb and hand-muscle involvement early in the disease course as well as the presence of Babinski signs with nonprogressive mild spastic paraparesis, resembling classic Silver syndrome and dHMN type V. This study reaffirms the clinical phenotype of the disorders associated with a BSCL2 Ser90Leu mutation and describes a genetically proven family with Silver syndrome and dHMN type V in Asia.     

Hereditary motor and sensory neuropathy type I and type II

In an attempt to clearly identify the different HMSN subgroups, we prospectively evaluated 128 subjects (46 index cases, 39 affected and 43 unaffected relatives) on clinical, genetic and electrophysiological grounds. The diagnosis of HMNS I or II was made in 77 patients. Differential diagnosis between type I and II patients was impossible on clinical grounds alone, but nerve conduction study showed a clearcut subdivision into two populations. MCV behavior was consistent within families. Inheritance, autosomal dominant in almost all cases, was probably recessive in three HMSN I subjects and pedigree analysis pointed to X-linked transmission in one HMSN I family. We found no evidence for linkage to Duffy locus. We think that similar HMSN phenotypes can be determined by different gene defects. Ulnar nerve F-conduction velocity did not significantly differ from distal MCV in HMSN I: the evidence of a diffuse slowing of nerve conduction supports the hypothesis of a primary myelin defect.

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Sommario Allo scopo di distinguere chiaramente in sottogruppi i pazienti affetti da HMSN, abbiamo studiato prospeticamente dal punto di vista clinico, genetico ed elettrofisiologico 128 soggetti: 46 casi indice, 39 parenti affetti e 43 sani. La diagnosi di HMSN I o II è state posta in 77 casi. La distinzione tra I e II tipo è risultata impossibile dal punto di vista clinico, ma lo studio delle velocità di conduzione ha dimostrato una chiara divisione in due popolazioni. Il comportamento delle VCM è risultato omogeneo all'interno delle singole famiglie. L'ereditarietà, autosomica dominante in quasi tutti i casi, è risultata probabilmente recessiva in tre soggetti con HMSN I, mentre l'analisi dell'albero genealogico suggerisce una trasmissione X-linked in un'altra famiglia di I tipo. Non abbiamo trovato linkage con il locus Duffy. In queste neuropatie fenotipi simili possono essere determinati da differenti difetti genici. La presenza di un diffuso rallentamento della conduzione nervosa periferica, evidenziata dal confronto tra velocità di conduzione della risposta Fe VCM del nervo ulnare depone per una patogenesi primitivamente mielinica dell'HMSN I.

     

Hereditary motor and sensory neuropathy type 1 (HMSN1) associated with cranial neuropathy: an autopsy case report

A family with hereditary motor and sensory neuropathy type 1 (HMSN1) is reported. Three patients suffered only pupillary abnormality, two patients showed Adie's syndrome and peripheral neuropathy, and one had cranial neuropathy. Adie's syndrome and severe peripheral neuropathy. Autopsy of the latter revealed reduction of myelinated nerve fibers in the trigeminal, facial and hypoglossal nerves. There was extensive degeneration of the posterior column of the spinal cord. At the anterior horns, loss of motor neurons was observed, particularly at the lumbar level. The anterior and posterior roots showed loss of myelinated fibers. HMSN1 is only rarely associated with cranial neuropathy, and this is probably the first autopsy-proved case.     

Hypertrophic type of peroneal muscular atrophy and spinal muscular atrophy in siblings

We describe a family with one brother suffering from a hypertrophic type of peroneal muscular atrophy, and a sister suffering from a late infantile from of spinal muscular atrophy. There are no other affected members in the relatives studied. This association has not been previously described, and has appeared as a result of a consanguineous marriage.     

腓骨肌萎缩症的病理和超微结构改变

目的　总结腓骨肌萎缩症 (HMSNⅠ型和Ⅱ型 )周围神经的病理改变及其特征。　　方法　采用单纤维分离、光镜及电镜观察 5例HMSNⅠ型、2例HMSNⅡ型腓肠神经的病理改变。　　结果　光镜下HMSNⅠ型患者大直径有髓纤维几乎完全消失 ,HMSNⅡ型部分保留 ,Ⅰ型各例均可见大量洋葱头样结构 ,Ⅱ型则无。电镜观察同样见到Ⅰ型患者有大量洋葱头样结构 ,并有较多膜性结构和雪旺氏细胞胞浆突起成分。Ⅱ型可见髓鞘坏变、塌陷 ,轴索内空泡变性。　　结论　HMSNⅠ型的基本病理改变为雪旺氏细胞病变 ,Ⅱ型则为轴索变性。     

Pudendal nerve involvement in patients with hereditary motor and sensory neuropathy

Pudendal nerve involvement was demonstrated by electromyography of perineal muscles and by recordings of their direct and reflex responses on perineal electrical stimulation in 10 patients with hereditary motor and sensory neuropathy. Patients reported no defecation disturbances and the 6 men had good erections. Urinary stress incontinence was seen in those 2 (of 4) female patients who had delivered.     

Hereditary motor and sensory neuropathy-Lom (HMSNL) in a Spanish family: clinical, electrophysiological, pathological and genetic studies

The clinical, electrophysiological, pathological and genetic findings are described in the first Spanish family diagnosed with hereditary motor and sensory neuropathy type Lom (HMSNL) initially identified by Kalaydjeva et al. in 1996. The three affected patients belong to a non-consanguineous family with Gypsy background that were followed up over 10 years. Serial clinical and neurophysiological examinations and genetic analysis were undertaken in every patient. Sural nerve biopsy was performed in the oldest patient. The clinical features are similar to those previously described in HMSNL and all of them showed abnormal brain auditory evoked potentials. The oldest brother developed sensorineural deafness at the age of 20. Conduction velocities were unobtainable in all patients and nerves tested except for the median nerve in the youngest child in whom conduction was severely slowed. Neuropathological examination revealed a severely depleted nerve with very few surviving myelinated fibers which possessed thin myelin sheaths. Schwann cell processes were arranged in circular configurations without typical onion bulb configuration. Genetic analysis showed that the maternal chromosome inherited by all three affected siblings displayed a very unusual haplotype. Our patients show the characteristic clinical, electrophysiological and pathological findings described in HMSNL and represent the first reported Spanish family affected from the disease. The genetic findings in this family have contributed to refine the HMSNL critical linkage region.     

Hereditary motor and sensory neuropathy (HMSN) and optic atrophy (HMSN type VI,Vizioli)

Summary Clinical and electrophysiological findings are described in three patients with hereditary motor and sensory neuropathy in association with optic atrophy (HMSN VI). The optic atrophy was of the Leber type in a 15-year-old boy. In a 70-year-old patient, as in three members of his family, optic atrophy was associated with tapetoretinal degeneration. In addition to HMSN and optic atrophy a 20-year-old man suffered from sensorineural deafness. Electrophysiological studies indicated a neuronal form of neuropathy, as in HMSN II. Brainstem auditory evoked potentials also revealed subclinical involvement of the central auditory pathways in the patients without hearing defects.Presented in part at the Working Meeting of the German Neurological Society (Arbeitstagung der Deutschen Gesellschaft für Neurologie), Essen, 24 September 1987     

Longitudinal conduction studies in hereditary motor and sensory neuropathy type 1

Motor conduction studies were performed serially in 10 patients, ages 10-62 years, with clinical and electrophysiological criteria of hereditary motor and sensory neuropathy type 1 (HMSN-1) over periods of 11-19 years. Median nerve conduction velocity (MNCV) and distal motor latency showed no significant change on serial studies. Mean median compound muscle action potential (CMAP) amplitude values, however, decreased 66% in 8 patients. Observed clinical progression in HMSN-1, over prolonged periods of time, was not associated with MNCV slowing. However, CMAP amplitude reduction, reflecting progressive axonal loss, correlated with clinical deterioration.     

Prevalence of hereditary motor and sensory neuropathy in Cantabria

One hundred and forty-four patients with hereditary motor and sensory neuropathy (HMSN) were selected from within a defined area (Cantabria) in Northern Spain, from 1974 to 1984. The series comprises 49 index cases and 95 affected relatives. The prevalence ratio was 28.2 cases per 100,000. The results of the study indicate that the majority of the cases were hereditary as a dominant trait. The prevalence for the Type I HMSN cases did not differ from that of Type II cases. Previous population-surveys of these disorders are compared.     

Conduction abnormalities induced by sera of patients with multifocal motor neuropathy and anti-GM1 antibodies

Increased titers of anti-GM1 antibodies have been associated with motor neuron disease and motor neuropathy with or without conduction block. To investigate the pathogenetic role of anti-GM1 antibodies we injected into rat tibial nerves sera from patients with multifocal motor neuropathy and conduction block (MMN) or progressive spinal muscular atrophy (PMA), both presenting anti-GM1 antibodies. Sera of patients with MMN produced reduction of amplitude and dispersion of compound muscle action potential from proximal stimulation. Morphometry revealed demyelination in 6.2% of fibers. Sera of patients with PMA did not produce clear-cut electrophysiological or morphological changes. Differential effects of sera from patients presenting high-titer anti-GM1 antibodies, but with distinct clinical syndromes, might depend on differences in anti-GM1 antibody affinity, valency, or ability to fix complement. Alternatively, circulating factors other than, or in addition to, anti-GM1 antibodies present in sera of patients with MMN, but not of PMA patients, might be responsible for conduction abnormalities and reproduce them after passive transfer. © 1993 John Wiley & Sons, Inc.     

远端型遗传性运动神经元病的分子遗传学研究进展

远端型遗传性运动神经元病(dHMN)是少见的遗传性周围神经病，特征是由于脊髓前角运动神经元退行性变引起对称性的肌无力和肌萎缩。dHMN是遗传性异质性疾病，呈常染色体显性遗传(AD)，也可呈常染色体隐性遗传(AR)或X连锁隐性遗传(XR)。dHMN的疾病基因已定位9型，其国5型已被克隆。     

Spinal muscular atrophy type I mimicking critical illness neuropathy in a paediatric intensive care neonate: electrophysiological features

We report the case of a neonate with spinal muscular atrophy type I (SMA type I or Werdnig-Hoffman disease) who was initially misdiagnosis as having critical illness neuropathy. Electromyography (EMG) showed a moderate loss of voluntary and motor unit potentials of both neurogenic and myopathic appearance. Nerve conduction studies revealed the presence of a severe sensory-motor axonal neuropathy. Finally, a biopsy of quadriceps was compatible with the diagnosis of SMA type I. A genetic study confirmed the existence of a homozygous absence of exons 7 and 8 of the telomeric supervival motoneuron gene (SMN1 gene).     

Clincial and pathological study of distal motor neuropathy with N88S mutation in BSCL2

Seipinopathy is an autosomal dominant inherited distal motor neuropathy caused by Berardinelli‐Seip congenital lipodystrophy 2 (BSCL2) gene mutations. We describe a Chinese family with seipinopathy in which nine patients from four successive generations were involved. The onset of age was from 13 to 40 years. Among them six were distal hereditary motor neuropathy type II with predominant weakness of lower extremities, while one of them was accompanied by pyramidal signs. The other three women were distal hereditary motor neuropathy type V with predominant atrophy of hands. Electrophysiological results in one patient demonstrated reduction of amplitude of compound muscle action potentials. Sural nerve biopsy showed loss of large myelinated fibers and fiber regeneration. Gene analysis revealed a heterozygous 263A→G mutation in BSCL2 gene resulting in amino acid substitutions in N88S. This report suggests that a different type of distal hereditary motor neuropathy could exist within one family carrying N88S mutations. The axonal degeneration of sensory nerves appeared also in the disease.     

RNA processing defects associated with diseases of the motor neuron

Rapid progress in the discovery of motor neuron disease genes in amyotrophic lateral sclerosis, the spinal muscular atrophies, hereditary motor neuropathies, and lethal congenital contracture syndromes is providing new perspectives and insights into the molecular pathogenesis of the motor neuron. Motor neuron disease genes are often expressed throughout the body with essential functions in all cells. A survey of these functions indicates that motor neurons are uniquely sensitive to perturbations in RNA processing pathways dependent on the interaction of specific RNAs with specific RNA‐binding proteins, which presumably result in aberrant formation and function of ribonucleoprotein complexes. This review provides a summary of currently recognized RNA processing defects linked to human motor neuron diseases. Muscle Nerve, 2010     

Mutual interference of myotonia and muscular dystrophy in the mouse: a study on ADR-MDX double mutants

For Duchenne muscular dystrophy (DMD, dystrophin deficiency) and Thomsen/Becker myotonia (muscular chloride channel deficiency) genetically homologous mouse models are available, the dystrophin-deficient MDX mouse and the myotonic ADR mouse. Whereas the latter shows more severe symptoms than human myotonia patients, the MDX mouse, in contrast to DMD patients, is only mildly affected. We have introduced, by appropriate breeding, the defect leading to myotonia (Clc1 null mutation, adr allele) into MDX mice, thus creating ADR-MDX double mutants. The expectation was that, due to mechanical stress during myotonic cramps, the ADR status should symptomatically aggravate the muscle fibre necrosis caused by the dystrophin deficiency. The overall symptoms of the double mutants were dominated by myotonia. Weight reduction and premature death rate were higher in ADR-MDX than in ADR mice. Sarcolemmal ruptures as indicated by influx into muscle fibres of serum globulins and injected Evans blue were found with great inter-individual variation in MDX and in ADR-MDX muscles. Affected fibres were found mainly in large groups in MDX but single or in small clusters in ADR-MDX leg muscles. The symptoms of myotonia (aftercontractions, shift towards oxidative fibres) were less pronounced in ADR-MDX than in ADR muscles. Conversely, numbers of damaged fibres as well as the percentage of central nuclei (an indicator of fibre regeneration) were significantly lower in ADR-MDX than in MDX skeletal muscles. Thus it appears that, at the level of the muscle fibre, myotonia and muscular dystrophy attenuate each other.     

进行性腓肌萎缩症（附一家系8例报告）

本文报告了一家系８例腓骨肌萎缩症。该家系四代３４人，患病８人（２３．５％），男女各半。７例于１０岁前发病。均符合遗传性运动和感觉性神经病Ⅰ型。其中２例经脊髓碘水造影加ＣＴ扫描发现腰骶部神经根增粗，作者认为本症的脑脊液蛋白增高可能与此有关。     

Psychiatric disorders appear equally in patients with myotonic dystrophy, facioscapulohumeral dystrophy, and hereditary motor and sensory neuropathy type I

OBJECTIVES: To study the presence of psychiatric comorbidity assessed by the use of a structured clinical interview and self-reported questionnaires in a large sample of patients with adult-onset myotonic dystrophy (DM), facioscapulohumeral muscular dystrophy (FSHD), and hereditary motor and sensory neuropathy type I (HMSN-I), and to assess whether psychiatric comorbidity is related to fatigue severity and/or muscle strength. METHODS: In a cohort of 217 patients with a neuromuscular disorder (79 DM, 65 FSHD and 73 HMSN-I patients) overall psychiatric comorbidity was studied cross-sectionally with the structured clinical interview for DSM-IV axis I disorders. Self-reported psychopathology, fatigue severity and muscle strength were assessed with the Beck Depression Inventory, Symptom Checklist-90, General Health Questionnaire-12, Checklist Individual Strength and muscle strength [Medical Research Council (MRC)-scale]. RESULTS: In all three neuromuscular disorders (DM, FSHD and HMSN), 10-12% of the patients met DSM IV clinical criteria for current psychiatric disorders. Lifetime psychiatric disorders were found in 32% of patients in all three patient groups. The most common psychiatric disorders were depression and phobias. A comparison of patients with and without current psychiatric disorder showed that fatigue severity and muscle strength (MRC) were not related to psychiatric comorbidity. CONCLUSION: Psychiatric disorders appear equally in patients with DM, FSHD and HMSN-I and are not related to fatigue or muscle strength in these patients.     

多灶性运动神经病的临床和电生理特征

目的研究多灶性运动神经病(MMN)的临床和电生理特征。方法回顾性分析16例MMN患者的临床资料和电生理检查结果。结果本组患者均为中青年起病,平均年龄(28.2±2.4)岁;16例患者均有非对称性四肢无力,肌力Ⅱ～Ⅳ级,上肢无力重于下肢,右侧重于左侧,4例有轻度肌萎缩,无感觉减退;肌电图检查发现所有患者均存在节段性运动神经传导阻滞(CB),病变神经的运动神经传导速度(MCV)均减慢,感觉神经传导速度(SCV)减慢1例。结论MMN是一种不对称的周围神经病,主要累及运动神经;神经电生理检查对诊断起重要作用,节段性运动神经CB是MMN特征性的神经电生理表现。