Genetically determined neuropathies

There have been major advances in the understanding of the genetically determined neuropathies in recent years. The underlying genetic defects are now known for many of the demyelinating hereditary motor and sensory neuropathies, and linkage data are available for some of the axonal hereditary motor and sensory neuropathies. This has important implications for both diagnosis and genetic counselling in this group of conditions. The genetic defect in most cases of familial amyloid polyneuropathy is also now known. In the most common form of familial amyloid polyneuropathy (FAP), transthyretin-related FAP, liver transplantation has been established as the first definitive treatment for a hereditary neuropathy and should be considered especially in young adult patients. This review will concentrate on the advances in the molecular genetics of the hereditary motor and sensory neuropathies, the hereditary sensory and autonomic neuropathies and the familial amyloid polyneuropathies with particular emphasis on the difficulties in classifying the first group. Received: 29 July 1997 Accepted: 2 September 1997     

Autosomal recessive type II hereditary motor and sensory neuropathy with acrodystrophy

A family is described with presumed autosomal recessive inheritance in which three siblings developed a progressive neuropathy that combined limb weakness and severe distal sensory loss leading to prominent mutilating changes. Electrophysiological and nerve biopsy findings indicated an axonopathy. The disorder is therefore classifiable as type II hereditary motor and sensory neuropathy (HMSN II). The clinical features differ from those reported in previously described cases of autosomal recessive HMSN II. This disorder may therefore represent a new variant. Received: 16 April 1998 Received in revised form: 26 June 1998 Accepted: 7 July 1998     

Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study

Central motor conduction to the small hand muscles was investigated in 59 patients with peroneal muscular atrophy and hereditary spastic paraplegia (HSP) by using transcranial magnetic brain stimulation. These comprised 20 patients with type I hereditary motor and sensory neuropathy (HMSN I), 15 with type II (HMSN II), 4 with HMSN I and 10 with HMSN II with associated pyramidal features, and 10 with the "pure" form of HSP. Central motor conduction was usually normal in HMSN I, HMSN II, and HSP. In HMSN I with pyramidal signs, central motor conduction time was greatly prolonged bilaterally. This result may reflect an associated involvement of the central motor pathways in these patients. In HMSN II with accompanying pyramidal features, 6 of the 10 patients had abnormal central motor conduction, although conduction times were only slightly prolonged, suggesting a different pathophysiological pattern.     

Hereditary spastic paraplegia associated with peripheral neuropathy: a distinct clinical and genetic entity

Hereditary motor and sensory neuropathy type V is a very rare disease in which hereditary spastic paraplegia is associated with peripheral motor and sensory neuropathy. The symptomatic onset of the disorder is usually in the second decade of life or later and the course is progressive over many years. Hereditary motor and sensory neuropathy type V is inherited as an autosomal dominant trait usually showing incomplete penetrance. So far, no molecular data are available in the literature about this disease. In our study we present clinical and molecular data from a large Italian family displaying hereditary motor and sensory neuropathy type V. Taking into account the clinical features in this family, we have performed a linkage analysis for markers strictly associated with all the known loci for autosomal dominant and autosomal recessive forms of hereditary spastic paraplegia and hereditary motor and sensory neuropathy type II, and have found no linkage to these loci. Our study suggests that hereditary motor and sensory neuropathy type V is not only a distinct clinical entity but also a distinct genetic entity.     

Autosomal recessive inheritance of hereditary motor and sensory neuropathy with optic atrophy.

Three siblings are reported with childhood onset hereditary motor and sensory neuropathy (HMSN) and adult onset optic atrophy. Electrophysiological studies showed an axonal neuropathy and dysfunction of the retinal ganglion cells or optic nerve. The presumed mode of inheritance is autosomal recessive. This is the second family in which autosomal recessive inheritance of HMSN and optic atrophy (HMSN type VI) has been described, and the first in which electrophysiological studies have been reported.     

Dominantly inherited leukodystrophy showing cerebellar deficits and spastic paraparesis: a new entity?

We studied a dominant hereditary disorder showing progressive spastic paraparesis. The symptoms began in early childhood, with cerebellar deficits and mild mental deterioration, and the subsequent appearance of limb spasticity resulted in severe disability in the 3rd-4th decades of life. None of the patients were associated with any somatic abnormalities. Brain MRI showed diffuse white-matter involevement in all affected patients, but not in unaffected siblings. Although dominant, recessive, or X-linked leukodystrophies cause similar clinical features, our family did not show any known biochemical or gene deficits characteristic of these disorders. The clinical, radiological, and biochemical findings of this family are reported and suggest a possible novel genetic disorder. Received: 25 September 1996 Received in revised form: 17 March 1997 Accepted: 6 April 1997     

线粒体融合蛋白2基因新突变导致的遗传性运动感觉性神经病6型一家系

目的 报道1个遗传性运动感觉性神经病6型家系的临床表现、病理改变以及基因突变特点。方法 先证者男性,15岁。患者5岁出现双下肢无力,症状进行性加重,伴随出现双足跟腱挛缩;11岁开始出现慢性进行性视力下降;12岁出现双手肌肉萎缩,无肢体麻木。周围神经传导速度检查显示诱发电位未能引出或波幅显著下降,感觉神经较运动神经改变更明显。视诱发电位提示双眼P100潜伏期均延长,波幅正常。眼底照相提示视神经萎缩,视网膜电图正常。患者母亲7岁时开始出现走路费力,10岁出现视力下降。对先证者进行腓肠神经活体组织检查。对先证者及其母亲进行线粒体融合蛋白2( MFN2)基因测序,100名健康人作为正常对照。结果 腓肠神经病理改变主要为有髓神经纤维显著减少,电镜检查发现个别有髓神经纤维出现洋葱球样结构和再生簇结构,个别神经纤维的轴索内可见线粒体聚集和空泡化。先证者和母亲的MFN2基因第19号外显子存在c.2218T＞C杂合突变,导致MFN2第740位的色氨酸由精氨酸替代(W740R)。100名健康对照没有发现该突变。结论 MFN2基因c.2218T＞C突变导致了遗传性运动感觉性神经病6型,其视力下降多出现在脊神经损害之后,周围神经可以存在髓鞘损害。     

Hereditary motor and sensory neuropathy with optic atrophy. Ultrastructural and morphometric observations on nerve fibers, mitochondria, and dense-cored vesicles

Nerve biopsy specimens from three cases of hereditary motor and sensory neuropathy with optic atrophy were studied by light and electron microscopy and by morphometry. All cases had a chronic neuropathy of the neuronal/axonal type with little, presumably secondary, demyelination. There was predominant reduction of the large-caliber population of myelinated and unmyelinated nerve fibers. The number of dense-cored vesicles in unmyelinated and small myelinated fibers was increased. Abnormal mitochondria in Schwann cells with paracrystalline inclusions, prominent cristae including paracrystalline material (cases 1 and 2), and axonal mitochondria with presumable hydroxyapatite crystals (case 3) were found. The morphologic results suggest that hereditary motor and sensory neuropathy with optic atrophy should be regarded as a separate entity within the hereditary motor and sensory neuropathy group.     

A family of hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V) presenting with phenotypic uniformity including onset in early childhood]

The proband was a 38 year old mother, who had begun to walk abnormally at one year old. She developed weakness and wasting in the intrinsic hand muscles in the third decades. On neurological examinations, she showed weakness with atrophy in the distal muscles of the upper and lower limbs, mild impairment of deep sensation in the feet, and severe spastic gait with scissoring. Deep tendon reflexes were hypoactive in the arms and at the ankles, and brisk at the knees. Babinski sign was present bilaterally. Nerve conduction studies revealed mild slowing of conduction velocities and reduction of muscle and sensory action potential amplitudes. Sural nerve biopsy showed a prominent decrease in myelinated fiber density, especially in the large fibers. Neither demyelination nor typical onion-bulb was found. Results of gene analysis of PMP-22 was negative. Her two daughters, 14- and 11-year-old, respectively, also presented with gait disturbance from the beginning of walking at one year old and had almost the same clinical manifestations as their mother, indicating autosomal dominant inheritance. This family of the hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V) was distinctive in having phenotypic uniformity including onset in early childhood.     

Troyer syndrome: a combination of central brain abnormality and motor neuron disease?

Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous disorders consisting of pure and complicated forms. A variant with the additional features of severe atrophy of the small hand muscles, dysarthria, mental retardation, and short stature has been termed Troyer syndrome (MIM#275900) after the name of Old Order Amish families suffering from these symptoms. We report here an Austrian family with two individuals who exhibit all the features of Troyer syndrome, and provide additional data on this disorder. Electrophysiological studies showed chronic denervation and reduced motor nerve conduction velocities but normal sensory potentials. Muscle biopsy revealed a neurogenic pattern while the sural nerve was normal on histological examination. Brain abnormalities on magnetic resonance imaging consisted of a thin corpus callosum with a poorly developed cingulate gyrus and mild periventricular signal hyperintensities. These findings characterize the Troyer syndrome as a disorder of the first and second motor neuron with additional damage in the brain. The morphological features observed in this family may contribute to the grouping and subsequent understanding of complicated forms of hereditary spastic paraplegia, together with similar observations in other, more recently reported families. Received: 24 September 1998 Received in revised form: 23 December 1998 Accepted: 30 December 1998     

Demyelinating sensorimotor neuropathy with congenital cataract, mental retardation, and unique, dysplastic perineurial cells within the endoneurium

We report on a 27-year-old Caucasian female with congenital cataract and mental retardation complaining of progressive paresis and atrophy of the lower legs beginning at the age of 16 years followed by atrophy of the thighs and small hand muscles. Motor and sensory conduction velocities (CV) of the upper and lower limbs were reduced (distal peroneal nerve: 21 m/s; median nerve: motor CV: 28 m/s, sensory CV 30 m/s). In the sural nerve biopsy specimens there were unique endoneurial cells immunoreactive for antibodies against the epithelial membrane antigen with multiple surface indentations and projections considered to be dysplastic perineurial cells. To the best of our knowledge these cells have not been reported in any other type of human peripheral neuropathy. The present case with the above clinical and structural findings appears to represent a new, complex, demyelinating type of a sporadic or possibly recessively inherited motor and sensory neuropathy. Received: 18 December 1998 / Revised, accepted: 9 March 1999     

Selective calf weakness suggests intraspinal pathology, not peripheral neuropathy

Four patients, referred as having peripheral neuropathy, were noted to be able to walk on their heels but not on their toes. In each, intraspinal disease was found: ependymoma of the filum terminale, spinal muscular atrophy, spinal stenosis, and meningeal carcinomatosis. By comparison, in 86 cases of hereditary motor and sensory neuropathy type 1, ankle plantar flexors were never weaker than ankle dorsiflexors. Patients with greater weakness in plantar flexors than in dorsiflexors should be suspected of having intraspinal disease rather than peripheral neuropathy. Physiologic and biomechanical factors may explain why muscles innervated by the peroneal nerve are weaker, or graded weaker, in peripheral neuropathy.     

Prevalence of subclinical neuropathy in diabetic patients: assessment by study of conduction velocity distribution within motor and sensory nerve fibres

Nerve conduction velocity distribution (CVD) study is a newly-developed electrodiagnostic method for detecting alterations in the composition of nerve fibres according to their conduction velocity. The presence of subclinical neuropathy was evaluated in 138 diabetic patients by CVD study of four motor nerves (external popliteal and ulnar nerves bilaterally) and two sensory nerves (median nerve bilaterally), and the data obtained were compared with standard electrophysiological parameters in the same nerve segments. CVD studies revealed an altered distribution pattern in 106 of 129 evaluable patients for motor nerves (82%) and in 67 of 115 evaluable patients for sensory nerves (58%), while standard examination gave abnormal findings in 92 of 137 patients (67%) and in 33 of 118 patients (11%), respectively. Of the patients adequately evaluated by both techniques, 21 of 129 patients (16%) revealed altered CVD data unaccompanied by slowing of maximum nerve conduction velocity, and 37 patients of 101 (37%) showed similar findings for sensory nerves. Subclinical alterations of motor and sensory nerve CVD were not significantly related to age or to metabolic control expressed as glycated haemoglobin levels; a significantly longer duration of disease was found in patients with motor and mixed subclinical neuropathy with respect to non-neuropathic patients. The CVD study allowed us to detect subclinical abnormalities of motor and sensory nerve fibres; often this is a more sensitive method than the standard electrodiagnostic study. This method can be very useful as a diagnostic tool and in research in the study of the progression of diabetic neuropathy. Received: 21 March 1997 Received in revised form: 8 September 1997 Accepted: 7 October 1997     

A family of hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V)

Three siblings with hereditary motor and sensory neuropathy with spastic paraplegia (HMN V) were described. Their grandfather was suspected to have the similar symptoms. Their parents were normal and not consanguineous. The first case was a 54-year-old woman. She has suffered from difficulty in walking since the age of 10 years. Distal muscular weakness and wasting began at 20 years old. She was admitted to our hospital for investigation in 1988. Results of examination of the brain, cranial nerve, and cerebellar function were normal. The deep reflexes were hyperactive in the arm and knee, while absent at the ankle. Babinski's sign was definitely positive. Muscular weakness and wasting were noted in intrinsic hand muscles and in those below her knees. There were pes cavus and hammer toes, and the gait was spastic. Mild sensory disturbance was noted in distal limbs. The conduction velocity of motor nerve fibers of her limbs was below normal and that of sensory nerve fibers normal. Muscle biopsy of biceps brachii revealed neurogenic changes. Sural nerve biopsy showed decreased number of myelinated fibers of large diameter and formation of small oinion-bulb. The second and third cases were her brothers and proven to have the similar condition, but their onset of illness were earlier and their affections were more severe. A few cases of HMSN V with nerve biopsy findings have so far been reported and the family presented here is the first report in Japan.     

Hereditary spastic paraplegia and axonal motor neuropathy caused by a novel SPG3A de novo mutation

Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia. Most patients with an SPG3A mutation present with a pure phenotype and early-onset disease, although complicated forms with peripheral neuropathy are also reported. We report a new heterozygous S398F mutation in exon 12 of the SPG3A gene causing a very early-onset spastic paraplegia in association with motor axonal neuropathy in a 4-year-old girl resembling diplegic cerebral palsy.     

Silver syndrome--case report

Silver syndrome (Silver spastic paraplegia syndrome) is a rare disorder of the peripheral nervous system that combines features of spastic paraparesis and peripheral neuropathy. The underlying genetic defects are two mutations in the BSCL2 gene which have been described in several families. Silver syndrome--related to the N88S mutation in the BSCL2 gene--is characterized by a spectrum of clinical findings. The coexistence of sensory fiber damage and motor deficit leads to the diagnosis of Charcot-Marie-Tooth disease in some patients, while others are diagnosed with spastic paresis due to predominant pyramidal symptoms. If the symptoms are limited to the motor deficit, hereditary motor neuropathy is diagnosed in some cases. In this report, we describe a case of the Silver syndrome in a Polish family that has been verified by genetic testing. Due to the lack of pyramidal symptoms and slightly expressed sensory fiber damage (in neurographic studies), motor neuropathy type of the Silver syndrome with minor sensory component was diagnosed.     

Hereditary motor and sensory neuropathy--Lom (HMSNL): refined genetic mapping in Romani (Gypsy) families from several European countries

Hereditary motor and sensory neuropathy type Lom, initially identified in Roma (Gypsy) families from Bulgaria, has been mapped to 8q24. Further refined mapping of the region has been undertaken on DNA from patients diagnosed across Europe. The refined map consists of 25 microsatellite markers over approximately 3 cM. In this collaborative study we have identified a number of historical recombinations resulting from the spread of the hereditary motor and sensory neuropathy type Lom gene through Europe with the migration and isolation of Gypsy groups. Recombination mapping and the minimal region of homozygosity reduced the original 3 cM hereditary motor and sensory neuropathy type Lom region to a critical interval of about 200 kb.     

The hereditary spastic paraplegias

The hereditary spastic paraplegias are a complex group of neurodegenerative conditions which are characterised by slowly progressive lower limb spasticity. This article describes the main clinical features of pure and complicated hereditary spastic paraplegias and summarises recent advances in our understanding of the molecular genetics of these conditions. Received: 2 June 1999 Accepted: 7 August 1999     

Early clinical and electrophysiologic features of the two most common autosomal recessive forms of Charcot-Marie-Tooth disease in the Roma (Gypsies)

Our recent studies of the genetic epidemiology of neuromuscular disorders in Gypsies in Bulgaria have revealed that two private disorders, hereditary motor and sensory neuropathy type Lom and hereditary motor and sensory neuropathy type Russe, account for most cases of Charcot-Marie-Tooth disease in this population. In this study, we examined the clinical and electrophysiologic manifestations of the two disorders in childhood, aiming to identify the distinctive features that allow early differential diagnosis. The study included 13 patients, aged between 2 and 15 years. The childhood clinical manifestations of both neuropathies were similar, although they tended to be more severe in hereditary motor and sensory neuropathy type Lom. The nerve conduction velocities in hereditary motor and sensory neuropathy type Lom were lower than in hereditary motor and sensory neuropathy type Russe. Brainstem auditory evoked potentials were abnormal in hereditary motor and sensory neuropathy type Lom, even at an early age, and normal in hereditary motor and sensory neuropathy type Russe. Although electrophysiologic data provide a more reliable differentiation than clinical data, the definitive diagnosis should rely on genetic testing. (J Child Neurol 2006;21:20-25).     

HMSN III phenotype due to homozygous expression of a dominant HMSN II gene.

We describe two siblings with hereditary motor and sensory neuropathy (HMSN) type III. Their parents were both affected with autosomal dominant axonal HMSN. The neuropathy in the siblings probably resulted from homozygous expression of the HMSN II gene. Together with other reports of homozygous HMSN I, this family suggests that HMSN III is heterogenous and encompasses the most severe homozygous expression of neuropathic genes.