A novel INF2 mutation in a Korean family with autosomal dominant intermediate Charcot‐Marie‐Tooth disease and focal segmental glomerulosclerosis

Mutations in the inverted formin‐2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot‐Marie‐Tooth (DI‐CMT) disease and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI‐CMT and FSGS by whole‐exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI‐CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS.     

Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2‐p12) deletion

Introduction: We describe a 6‐year‐old girl with a T118M PMP22 mutation and heterozygous deletion of PMP22 on chromosome 17 (17p11.2‐p12) resulting in a severe sensorimotor polyneuropathy. Methods: This study is a case report in which the relevant mutations are described. Results: Foot pain, cavovarus feet, tibialis anterior atrophy, absent reflexes, and inability to walk were found when the patient was age 6 years. Nerve conduction studies showed evidence of a sensorimotor polyneuropathy and compressive mononeuropathies of bilateral median nerves at the wrist and ulnar nerves at the elbow. Genetic testing revealed deletion of a PMP22 allele and T118M PMP22 mutation in the remaining allele. Conclusions: The severe sensorimotor polyneuropathy and hereditary neuropathy with liability to pressure palsies (HNPP) in this patient was likely a consequence of both decreased expression of PMP22 causing features consistent with HNPP and unopposed expression of the T118M mutant form of PMP22 that is relatively benign in the heterozygous state. The T118M mutant form of PMP22 can be disease‐modifying in the appropriate circumstances. Muscle Nerve 52 : 905–908, 2015     

A novel small deletion in PMP22 causes a mild hereditary neuropathy with liability to pressure palsies phenotype

Introduction: In this study we examined a family with electrophysiological findings of hereditary neuropathy with liability to pressure palsies (HNPP) and a mild clinical presentation.Methods: Four members of a family were referred for diagnosis of HNPP. Electrophysiological studies included motor and sensory nerve conduction studies in the upper and lower extremities. Investigations of microsatellites, using polymorphic repeat markers flanking the gene, and multiplex ligation‐dependent probe amplification (MLPA) were performed for molecular studies. Results: The initial study of microsatellites did not detect any change, but MLPA demonstrated a small deletion of exon 5 in the PMP22 gene. Conclusion: Our findings demonstrate the important role of small deletions in the PMP22 gene in the etiology of HNPP with a normal microsatellite study. Muscle Nerve 45: 135–138, 2012     

A case of familial amyloid polyneuropathy homozygous for the transthyretin Val30Met gene with motor-dominant sensorimotor polyneuropathy and unusual sural nerve pathological findings.

OBJECTIVE: To report a case of familial amyloid polyneuropathy homozygous for the amyloidogenic transthyretin (ATTR) Val30Met gene with motor-dominant sensorimotor polyneuropathy and unusual sural nerve pathological findings. METHODS: Mass spectrometry analysis and polymerase chain reaction-restricting fragment length polymorphism were performed. A right sural nerve biopsy specimen was obtained for histological investigation. SETTING: Academic medical center. RESULTS: A 56-year-old Japanese man living in a local town (Nakajima, Japan) in Ishikawa Prefecture, a nonendemic area of type I familial amyloidotic polyneuropathy, had vitreous amyloidosis, motor-dominant sensorimotor polyneuropathy, erectile dysfunction, and urinary incontinence. He had neither orthostatic hypotension nor indolent diarrhea. Restriction enzyme analysis with EcoT22 I of amplified DNA and mass spectrometry analysis revealed homozygosity for ATTR Val30Met. Of 8 family members, 5 were evaluated and found to be heterozygous for ATTR Val30Met; a family history found no relative with the similar neurologic disorders. The sural nerve biopsy specimen showed focal edema and an amyloid deposit in the subperineural tissue, associated with moderate loss of myelinated and unmyelinated fibers. CONCLUSIONS: In addition to the findings characteristic of homozygosity for ATTR Val30Met such as vitreous amyloidosis and relatively less autonomic involvements, this case had the unique findings of motor-dominant sensorimotor polyneuropathy and unusual sural nerve biopsy specimen results.     

河南地区两个腓骨肌萎缩症家系PMP22基因突变研究

目的分析在河南地区两个腓骨肌萎缩症(CMT)家系的临床表现及PMP22基因重复突变的特点。方法收集两家系中21名成员的临床资料,并应用等位基因特异性PCR-双酶切方法检测17p11.2-1 PMP22基因重复(即1760 bp片段)序列的情况,同时选择50名健康人做为对照。结果两家系中共14名成员经等位基因特异性PCR-双酶切方法检测出PMP22基因大片重复(即1760 bp片段)序列;家系一患病者有3名(Ⅱ5、Ⅱ7、Ⅲ11),无临床症状但基因检测结果示PMP22基因重复突变为携带者有6名(Ⅱ9、Ⅲ6、Ⅲ8、Ⅲ10、Ⅳ1、Ⅳ2);家系二患病者有4名(Ⅱ3、Ⅱ9、Ⅱ11、Ⅲ7),携带者只有Ⅲ5。两家系中余7人及健康对照50人均未检测出上述重复突变。结论 PCR-双酶切法检测PMP22特异性基因重复序列在早期诊断CMT有重要价值。     

PMP22‐Related neuropathies and other clinical manifestations in Chinese han patients with charcot‐marie‐tooth disease type 1

Introduction: Most cases of Charcot‐Marie‐Tooth (CMT) disease are caused by mutations in the peripheral myelin protein 22 gene (PMP22), including heterozygous duplications (CMT1A), deletions (HNPP), and point mutations (CMT1E). Methods: Single‐nucleotide polymorphism (SNP) arrays were used to study PMP22 mutations based on the results of multiplex ligation‐dependent probe amplification (MLPA) and polymerase chain reaction–restriction fragment length polymorphism methods in 77 Chinese Han families with CMT1. PMP22 sequencing was performed in MLPA‐negative probands. Clinical characteristics were collected for all CMT1A/HNPP probands and their family members. Results: Twenty‐one of 77 CMT1 probands (27.3%) carried duplication/deletion (dup/del) copynumber variants. No point mutations were detected. SNP array and MLPA seem to have similar sensitivity. Fifty‐seven patients from 19 CMT1A families had the classical CMT phenotype, except for 1 with concomitant CIDP. Two HNPP probands presented with acute ulnar nerve palsy or recurrent sural nerve palsy, respectively. Conclusions: The SNP array has wide coverage, high sensitivity, and high resolution and can be used as a screening tool to detect PMP22 dup/del as shown in this Chinese Han population. Muscle Nerve 52 : 69–75, 2015     

Report of a novel mutation in the PMP22 gene causing an axonal neuropathy

Introduction: Point mutations in the peripheral myelin protein 22 (PMP22) gene rarely cause the hereditary neuropathies Charcot–Marie–Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), both of which show a demyelinating phenotype. Methods: In this study we characterized a family with an axonal neuropathy. Results: Three family members carried a heterozygous point mutation of the PMP22 gene, resulting in amino acid substitution R159C. Screening of 185 healthy controls did not reveal the R159C allele in any case. Discussion: The novel R159C mutation represents a very rare case of a dominant PMP22 mutation causing an axonal neuropathy. Muscle Nerve, 2011     

Phe 84 deletion of the PMP22 gene associated with hereditary motor and sensory neuropathy HMSN III with multiple cranial neuropathy: clinical, neurophysiological and magnetic resonance imaging findings

Hereditary motor and sensory neuropathy (HMSN) is a heterogeneous group of peripheral neuropathies which are diagnosed on the basis of clinical, electrophysiological and neuropathological findings. Among the hypertrophic demyelinating neuropathies, HMSN III is the most severe. It is often associated with de novo mutations in the genes encoding for peripheral myelin proteins. While peripheral nerve hypertrophy is an expected finding in HMSN III, cranial nerve hypertrophy is exceptional. Here we describe a mutation in the PMP22 gene in a 19-year-old man with infantile onset of sensory motor polyneuropathy without family history and multiple cranial nerve hypertrophy shown by cranial magnetic resonance imaging. Received: 3 May 2000, Received in revised form: 29 August 2000, Accepted: 7 September 2000     

家族性淀粉样多发性神经病一家系病理及基因点突变

目的　对我国首次报道的家族性淀粉样多发性神经病（FAP）家系进行各项研究,以期发现其真正类型。方法　对我国东北某地一家系67人共16例多发性周围神经病患者进行详尽的临床检查,对其中2例患者进行腓肠神经病理检查,和转甲蛋白(TTR)基因的聚合酶链反应(PCR)基因扩增及直接法测序分析。结果　临床上该家系所有患者均以植物神经症状,如排尿障碍、胃肠道症状、阳痿为首发症状。体格检查提示为严重的感觉运动神经病、体位性低血压和消瘦。病理学检查发现2例患者均有刚果红染色阳性的大量淀粉样物沉积于神经束间质及神经内膜中。免疫组化证实淀粉样物与TTR有关。PCR扩增产物酶解及直接法测序,确定异常TTR为基因点突变所致,突变位置为日本及葡萄牙型FAP常见的第二个外显子第30个密码子G由A取代。结论　本研究结果证实,该家系为Met30FAP,填补了我国对该疾病研究的空白。     

Familial polyneuropathy with a disposition to pressure paralyses. A contribution to the differential diagnosis of mononeuropathies

When a young woman admitted for recurrent peripheral nerve palsies was suspected to suffer from hereditary polyneuropathy with liability to pressure palsies, 8 members of her family were examined diagnostically. Only one of these had a history of a transient mononeuropathy. A neurophysiological examination demonstrated peripheral nerve lesions not only in the patients father but also in 5 of her brothers and sisters. In presenting the data for this family the characteristics of hereditary polyneuropathy with liability to pressure palsies and the most important differential diagnostic aspects are discussed.     

Parental mosaicism of a novel PMP22 mutation with a minimal neuropathic phenotype

Genetic germinal and somatic mosaicisms of dominant Charcot‐Marie‐Tooth disease (CMT) mutations are rarely reported and/or recognized. We describe a novel heterozygous p.Trp39Cys missense mutation in the extracellular domain of the peripheral myelin protein 22 (PMP22) associated with an early‐onset demyelinating CMT type 1 E (CMT1E) in two siblings born from asymptomatic non‐consanguineous parents. The 29‐year‐old mother, harboring approximately 20% of the mutant PMP22 allele in blood, had minor signs of distal polyneuropathy (pes cavus, decreased ankle jerk reflexes and vibration sense in legs) and slight reduction of sural nerve action potentials (SNAPs). Authors suggest that mutations of CMT‐related genes which originate in post‐zygotic stages may be associated with mild phenotypes of peripheral neuropathy.     

Homozygous splice‐site mutation c.78 + 5G>A in PMP22 causes congenital hypomyelinating neuropathy

Congenital hypomyelinating neuropathy (CHN) presents in the neonatal period and results in delayed development of sensory and motor functions due to several gene mutations including in EGR2, MPZ, CNTNAP1, and PMP22. The phenotype of homozygous splice‐site mutation in the PMP22 gene has not been described in humans or animal models. Here we describe a family carrying a pathogenic splice‐site c.78 + 5G>A mutation in the PMP22 gene. We evaluated the clinical, electrophysiological, histological, and genetic features of the family. The proband with homozygous mutation presented with CHN, while his consanguineous parents with heterozygous mutation were asymptomatic. The proband was a 7‐year‐old boy. He had motor retardation after birth and had remained unable to walk independently at the time of the study. The compound muscle action potentials and sensory nerve action potentials were not recordable in the boy. The motor and sensory nerve conduction velocities of the parents were slightly to moderately decreased, although they had no symptoms of peripheral neuropathy. The sural nerve biopsy of the boy revealed hypomyelinating neuropathy with absence of large myelinated fibers, no myelin breakdown products, and numerous basal lamina onion bulb formations. To our knowledge, this is the first report of a homozygous splice‐site mutation in the PMP22 gene in humans. Our study expands the phenotype and genotype of PMP22‐related neuropathy.     

A novel stop codon mutation in the PMP22 gene associated with a variable phenotype

The most frequent inherited peripheral neuropathy is the peripheral myelin protein 22 (PMP22) gene related disease. Duplication, deletion, and point mutations in that gene are associated with phenotypic variability. Here we report a family carrying a novel mutation in the PMP22 gene (c. 327C>A), which results in a premature stop codon (Cys109stop). The family members who carry this mutation have a Charcot-Marie-Tooth type 1 variable phenotype, ranging from asymptomatic to severely affected. These findings suggest that the fourth transmembrane domain of the PMP22 gene may play an important role, although the intrafamilial clinical variability reinforces the observation that pathogenic mutations are not always phenotype determinant and that other factors (genetic or epigenetic) modulate the severity of the clinical course.     

A novel mutation of myelin protein zero associated with late-onset predominantly axonal Charcot-Marie-Tooth disease

We report a case of late-onset predominantly axonal Charcot-Marie-Tooth disease resulting from a novel mutation in the MPZ gene encoding myelin protein zero (P0). Neurological examination, electrophysiological examination and genetic testing were performed on three members of a Finnish family (family A) and one member of a German family (family B). Three other members of the Finnish family were interviewed and genetically tested. Genetic testing was also performed on 95 healthy Finnish controls. Three members in two generations of family A and the member of family B were affected with late-onset axonal more than demyelinating, motor and sensory polyneuropathy. Heterozygous c.316C>T mutation in MPZ leading to p.Arg106Cys in P0 was found in all the affected subjects, but not in the three unaffected members of the Finnish family. None of 95 healthy Finnish controls harbored the mutation. The findings of this study indicate that p.Arg106Cys allele in MPZ causes late-onset predominantly axonal sensory and motor neuropathy.     

Phenotypic heterogeneity in a family with FAP due to a TTR Leu58Arg mutation: a clinicopathologic study

A family with familial amyloid polyneuropathy (FAP) due to a transthyretin (TTR) Leu58Arg mutation was investigated clinicopathologically. The proband presented with sensorimotor-autonomic polyneuropathy and autopsy demonstrated massive amyloid deposition in the peripheral nerves and heart. However, the mother was characterized by carpal tunnel syndrome and ocular vitreous opacities. Thus, there was considerable phenotypic heterogeneity among family members despite the identical TTR genotype.     

Autosomal dominant cerebellar ataxia with slow ocular saccades,neuropathy and orthostatism: A novel entity?

BackgroundWe describe the clinical characteristics of a Swedish family with autosomal dominant cerebellar ataxia, sensory and autonomic neuropathy, additional neurological features and unknown genetic cause.MethodsFourteen affected family members were identified. Their disorder was characterized by neurological examination, MRI, electroneurography, electromyography, MIBG-scintigraphy, and tilt-testing.ResultsThe disorder presented as a balance and gait disturbance starting between 16 and 47 years of age. Cerebellar ataxia progressed slowly over the course of decades, and MRI showed mild to moderate cerebellar atrophy. Sensory axonal polyneuropathy was the most prominent additional feature and occurred in all patients examined. Autonomic neuropathy caused pronounced orthostatic dysregulation in at least four patients. Several affected members showed muscle wasting, and mild upper or lower motor neuron signs were documented. Patients had no nystagmus but slow or hypometric horizontal saccades and ocular motor apraxia. Cognition remained unimpaired, and there were no non-neurological disease manifestations. The disorder affected men and women in successive generations in a pattern compatible with autosomal dominant inheritance without evidence of anticipation. A second family where 7 members had very similar symptoms was identified and its origin traced back to the same village in southern Sweden as that of the first family's ancestors. All relevant known genetic causes of cerebellar ataxia were excluded by a novel next-generation sequencing approach.ConclusionWe present two probably related Swedish families with a characteristic and novel clinical syndrome of cerebellar ataxia and sensory polyneuropathy. The study serves as a basis for the mapping of the underlying genetic cause.     

Familial partial epilepsy with variable foci: A new family with suggestion of linkage to chromosome 22q12

Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant form of partial epilepsy characterized by the presence of epileptic seizures originating from different cerebral lobes in different members of the same family. Linkage to chromosomes 22q12 and 2q36 has been reported, although only six families have been published. We studied a new FPEVF family including nine affected individuals. The phenotype in this family was similar to that previously described and consisted of nocturnal and daytime seizures with semiology suggesting a frontal lobe origin. A video‐EEG (electroencephalography) recording of the proband’s seizures is presented and revealed hyperkinetic seizures of frontal lobe origin preceded by left frontal spikes. We excluded linkage to chromosome 2q36 and found a suggestion of linkage to chromosome 22q12 with a lod score of 2.64 (θ = 0) for marker D22S689.     

Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy

A white British family with the axonal form of hereditary motor and sensory neuropathy (HMSN, type II) contained one member who developed a recurrent laryngeal nerve palsy at the age of 41 years, in addition to 4 years of symptomatic polyneuropathy and an abducens nerve palsy. Neither of the other family members (the mother and sister) with electrophysiologically confirmed polyneuropathy had any neuropathic symptoms in the limbs or laryngeal or respiratory muscle involvement. An autosomal dominant pattern of inheritance is likely. This is a second report of this rare form of HMSN (type IIC) in which there is associated laryngeal or respiratory muscle weakness. This family differs from the two previously reported pedigrees in which laryngeal or diaphragm weakness had commenced within the first two decades. The discovery of asymptomatic family members attests to the diagnostic value of clinical and electrophysiological study of first-degree relatives when laryngeal or bulbar symptoms develop in the context of chronic axonal polyneuropathy. HMSN type IIC should be distinguished from the more common forms of HMSN – type IIA, in which axonal polyneuropathy is restricted to the limbs, and type IIB, which is of early onset and associated with foot ulceration. Received: 10 July 1998 Received in revised form: 8 December 1998 Accepted: 10 December 1998     

Hereditary amyloidosis of the Finnish type in a German family: Clinical and electrophysiological presentation

Hereditary amyloidosis of the Finnish type (HAF, or familial amyloid polyneuropathy type IV) is an autosomal dominant disease that has been described most commonly in the Finnish population but has also been found in some other countries. Herein we report the first German family whose members suffer from this condition. There are no known Finnish ancestors. We performed clinical and electrophysiological examinations in 22 members of this family. All symptomatic family members suffered from facial palsy, and most of them had peripheral neuropathy. One patient had confirmed corneal lattice dystrophy. Additional symptoms were hypoglossal nerve involvement in 5 patients and oculomotor nerve palsy in 1 patient. The lips of all older patients appeared thickened. The causative G654A mutation in the gelsolin gene was found in all affected family members. Muscle Nerve, 2010