MFN2 deletion of exons 7 and 8: founder mutation in the UK population

Mitofusin 2 (MFN2) mutations are the most common cause of axonal Charcot‐Marie‐Tooth disease (CMT2). The majority are inherited in an autosomal dominant manner but recessive and semi‐dominant kindreds have also been described. We previously reported a deletion of exons 7 and 8 resulting in nonsense‐mediated decay, segregating with disease when present in trans with another pathogenic MFN2 mutation. Detailed clinical and electrophysiological data on a series of five affected patients from four kindreds and, when available, their parents and relatives were collected. MFN2 Sanger sequencing, multiplex ligation probe amplification, and haplotype analysis were performed. A severe early‐onset CMT phenotype was seen in all cases: progressive distal weakness, wasting, and sensory loss from infancy or early childhood. Optic atrophy (four of five) and wheelchair dependency in childhood were common (four of five). All were compound heterozygous for a deletion of exons 7 and 8 in MFN2 with another previously reported pathogenic mutation (Phe216Ser, Thr362Met, and Arg707Trp). Carrier parents and relatives were unaffected (age range: 24–82 years). Haplotype analysis confirmed that the deletion had a common founder in all families.     

KIF1A‐related disorders in children: A wide spectrum of central and peripheral nervous system involvement

KIF1A‐related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood‐onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case‐notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent—but sometimes progressive—changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.     

Spinal charcot‐marie‐tooth disease: A reappraisal

Introduction: Distal hereditary motor neuropathy (dHMN) is characterized by isolated distal muscle atrophy without sensory deficit. Nevertheless, clinical sensory loss has been reported despite preserved sensory nerve conduction in a few patients, thus differentiating these cases from the classical type 2 Charcot‐Marie‐Tooth disease (CMT2). Methods: We report 4 patients who presented with clinical sensory and motor neuropathy and normal peripheral sensory nerve conduction studies and were investigated with complete electrophysiological studies, including somatosensory evoked potentials (SEP). Results: These patients had a clinical presentation of classical CMT with isolated axonal motor neuropathy suggestive of dHMN. Interestingly, tibial nerve SEPs showed abnormalities suggestive of proximal involvement of dorsal roots that may explain the clinical somatosensory disturbances. Conclusions: These cases support the concept of spinal CMT that should be recognized as an intermediate form between dHMN and CMT2. SEP recording was helpful in defining a more precise phenotype of spinal CMT. Muscle Nerve 46: 603–607, 2012     

Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation

ATP1A3, the gene encoding the α3‐subunit of the Na⁺/K⁺‐ATPase pump, has been involved in four clinical neurological entities: (1) alternating hemiplegia of childhood (AHC); (2) rapid‐onset dystonia parkinsonism (RDP); (3) CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; and (4) early infantile epileptic encephalopathy. Here, we report on a 34‐year‐old female presenting with a new ATP1A3‐related entity involving a relapsing encephalopathy characterized by recurrent episodes of cerebellar ataxia and altered consciousness during febrile illnesses. The term RECA is suggested – relapsing encephalopathy with cerebellar ataxia. The phenotype of this patient, resembling mitochondrial oxidative phosphorylation defects, emphasizes the possible role of brain energy deficiency in patients with ATP1A3 mutations. Rather than multiple overlapping syndromes, ATP1A3‐related disorders might be seen as a phenotypic continuum.     

Clinical and genetic diversities of Charcot‐Marie‐Tooth disease with MFN2 mutations in a large case study

Charcot‐Marie‐Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1,334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 ± 14 (range 0–59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co‐occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is the most frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2‐related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity.     

A novel ARX phenotype: rapid neurodegeneration with Ohtahara syndrome and a dyskinetic movement disorder

ARX mutations are associated with variable clinical phenotypes. We report a new neurodegenerative phenotype associated with a known ARX mutation and causing early abnormal neurodevelopment, a complex movement disorder, and early infantile epileptic encephalopathy with a suppression‐burst pattern (Ohtahara syndrome). A male infant presented at age 5 months with a dyskinetic movement disorder, which was initially diagnosed as infantile spasms. Clinical deterioration was accompanied by progressive cortical atrophy with a reduction in white matter volume and resulting in death in the first year of life; such a rapidly progressive and severe phenotype has not previously been described. ARX mutation testing should be undertaken in children aged less than 1 year with Ohtahara syndrome and a movement disorder, and in infants with unexplained neurodegeneration, progressive white matter loss, and cortical atrophy.     

Hereditary sensory autonomic neuropathy type II: Report of two novel mutations in the FAM134B gene

Hereditary sensory autonomic neuropathy (HSAN) type II is a rare, autosomal recessive, and early onset sensory neuropathy, characterized by severe and progressive sensation impairment, leading to ulcero‐mutilating complications. FAM134B gene, also known as RETREG1 gene, mutations have been reported to be associated to HSAN‐IIB. We report four patients from two unrelated families who developed during childhood a sensory axonal neuropathy with variable severity and pronounced nociception impairment. Complications such as recurrent ulcerations, osteomyelitis, and osteonecrosis leading to distal amputation were noticed. Dysautonomia was mild or even absent in our group of patients. Additionally, either clinical or neurophysiological motor impairment was not uncommon. Presence of upper motor neuron signs was also a distinctive feature in two related patients. After extensive workup, two novel homozygous mutations in the FAM134B gene were identified. This report expands the clinical and genetic spectrum of HSAN type II and emphasizes the phenotype variability even within the same family.     

Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large,multigenerational North American family

Introduction: Distal hereditary motor neuropathy (dHMN) causes distal‐predominant weakness without prominent sensory loss. Myosin heavy chain disorders most commonly result in distal myopathy and cardiomyopathy with or without hearing loss, but a complex phenotype with dHMN, myopathy, hoarseness, and hearing loss was reported in a Korean family with a c.2822G>T mutation in MYH14. In this study we report phenotypic features in a North American family with the c.2822G>T in MYH14. Methods: Clinical and molecular characterization was performed in a large, 6‐generation, Caucasian family with MYH14 dHMN. Results: A total of 11 affected and 7 unaffected individuals were evaluated and showed varying age of onset and severity of weakness. Genotypic concordance was confirmed with molecular analysis. Electrophysiological studies demonstrated distal motor axonal degeneration without myopathy in all affected subjects tested. Conclusion: Mutation of MYH14 can result in a range of neuromuscular phenotypes that includes a dHMN and hearing loss phenotype with variable age of onset. Muscle Nerve 56 : 341–345, 2017     

Clinical spectrum of AIFM1‐associated disease in an Irish family,from mild neuropathy to severe cerebellar ataxia with colour blindness

Mutations in apoptosis‐inducing factor mitochondrion‐associated‐1 (AIFM1) cause X‐linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described. We describe a large Irish family with seven affected males. They presented with a variable age of onset, 18 months to 39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia, and pyramidal involvement. In addition, three had colour vision deficiency. Scale for the assessment and rating of ataxia ranged 2 to 23/40, while Charcot‐Marie‐Tooth neuropathy score 2 varied between 7 and 13/36. All individuals had normal cognitive assessment. Neurophysiology demonstrated length‐dependent large‐fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Four obligate female carriers were assessed clinically, two of them neurophysiologically; all were unaffected. Whole genome sequencing demonstrated a previously reported hemizygous AIFM1 mutation. Analysis for mutations in other genes associated with colour deficiency was negative. AIFM1‐associated phenotype in this family demonstrated significant variability. To our knowledge, this is the first report of AIFM1‐associated colour blindness. Superficial radial nerve was particularly affected neurophysiologically, which could represent a phenotypic marker towards this specific genetic diagnosis.     

Hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy: report on a family

We describe two siblings affected by a motor and sensory neuropathy starting in childhood. Already in infancy, a spastic gait disturbance had become obvious, leading later to multiple surgical interventions. In adolescence, progressive loss of vision developed. At the time of our examination, both siblings showed severe weakness and atrophy of the distal muscles of legs and arms. Tendon jerks were brisk in proximal muscles; in the lower extremities, muscle tone was increased. Visual acuity was severely decreased. Nerve conduction studies revealed an axonal degeneration. This finding was confirmed by evaluation of a sural biopsy specimen in one patient, showing only few remaining myelinated fibres without signs of demyelination. This combination of hereditary motor and sensory neuropathy with spastic paraplegia and optic atrophy shows features of both hereditary motor and sensory neuropathy V and VI according to the classification of Dyck, indicating that these subtypes may not represent distinct entities. Received: 24 February 1997 Received in revised form: 30 May 1997 Accepted: 26 July 1997     

Two novel mutations of GARS in Korean families with distal hereditary motor neuropathy type V

Glycyl‐tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot‐Marie‐Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN‐V). We performed whole exome sequencing (WES) to identify the genetic defects in the two dHMN families. WES revealed several decades of non‐synonymous variants in the CMT and aminoacyl‐tRNA synthetase genes. The subsequent capillary sequencing for family members and controls revealed two novel causative mutations, c.598G>A (D200N) and c.794C>T (S265F), in the GARS gene in each dHMN family. Both mutations were cosegregated with affected individuals in each family, and were not found in the 200 controls. The mutation sites were well conserved between the different species and in silico analysis predicted that both mutations may affect protein function. Therefore, we believe that these two novel GARS mutations are the underlying causes of the dHMN phenotype.     

Nerve conduction studies in spastic paraplegia,optic atrophy,and neuropathy (SPOAN) syndrome

Introduction: SPOAN (spastic paraplegia, optic atrophy, and neuropathy) syndrome is an autosomal recessive neurodegenerative disorder identified in a large consanguineous Brazilian family. Methods: Twenty‐seven patients with SPOAN syndrome (20 women), aged 4–58 years, underwent nerve conduction studies (NCS) of the median, ulnar, tibial, and fibular nerves, and sensory NCS of the median, ulnar, radial, sural, and superficial fibular nerves. Results: Sensory nerve action potentials were absent in the lower limbs and absent in >80% of upper limbs. Motor NCS had reduced amplitudes and borderline velocities in the upper limbs and absent compound muscle action potentials (CMAPs) in the lower limbs. Conclusions: The neuropathy in SPOAN syndrome is a severe, early‐onset sensory–motor axonal polyneuropathy. Normal NCS seem to rule‐out this condition. Muscle Nerve 49 : 131–133, 2014     

PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies

BackgroundProgressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research.MethodsWe enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis.ResultsWe identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novo GNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy.ConclusionsWe hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.     

Expanding the spectrum of SPTLC1‐related disorders beyond hereditary sensory and autonomic neuropathies: A novel case of the distinct “S331 syndrome”

Hereditary sensory and autonomic neuropathies (HSAN) encompass a group of peripheral nervous system disorders characterized by remarkable heterogeneity from a clinical and genetic point of view. Mutations in SPTLC1 gene are responsible for HSAN type IA, which usually starts from the second to fourth decade with axonal neuropathy, sensory loss, painless distal ulcerations, and mild autonomic features, while motor involvement usually occur later as disease progresses. Beyond the classic presentation of HSAN type IA, an exceedingly rare distinct phenotype related to SPTLC1 mutations at residue serine 331 (S331) has recently been reported, characterized by earlier onset, prominent muscular atrophy, growth retardation, oculo‐skeletal abnormalities, and possible respiratory complications. In this report, we describe clinical, instrumental, and genetic aspects of a 13‐year‐old Sri Lankan male carrying the rare de novo p.S331Y heterozygous mutation in SPTLC1 gene found by whole exome sequencing. Patient's phenotype partly overlaps with the first case previously reported, however with some additional features not described before. This work represent the second report about this rare mutation and our findings strongly reinforce the hypothesis of a clearly distinct “S331 syndrome”, thus expanding the spectrum of SPTLC1‐related disorders.     

A novel mutation of LRSAM1 in a Chinese family with Charcot‐Marie‐Tooth disease

Charcot‐Marie‐Tooth (CMT) disease is the most common inherited peripheral neuropathy characterized by progressive distal muscle weakness and atrophy with decreased or absent tendon reflexes. Mutations in LRSAM1 have been identified to cause CMT disease type 2P. We report a novel LRSAM1 mutation c.2021‐2024del (p.E674VfsX11) in a Chinese autosomal dominant CMT disease type 2 family. The phenotype was characterized by late onset and mild sensory impairment. Electrophysiological findings showed normal or mildly to moderately reduced motor and sensory nerve conduction velocities in lower and upper limb nerves.     

Truncating CLCN1 mutations in myotonia congenita: Variable patterns of inheritance

Introduction: Myotonia congenita due to protein truncating CLCN1 mutations is associated with variable patterns of inheritance. Methods: Three family kindreds are described, all of whom possess protein truncating mutations (Y33X, fs503X, R894X). One lineage also has coexistent R894X, A313T, and A320V mutations. Results: The Y33X mutation kinship has autosomal recessive inheritance and a severe phenotype when homozygous. The fs503X family has autosomal dominant inheritance and a moderate‐to‐severe phenotype. The A313T mutation kindred also has autosomal dominant inheritance but expresses a mild phenotype, except for the more severely affected compound heterozygotes. Conclusions: Early truncating mutations precluding dimerization are expected to be autosomal recessive and express a severe phenotype, while later mutations may be variable. The pedigrees presented here demonstrate that intrafamilial phenotypic variability may result from a dosage effect of an additional mutation, not necessarily variable expressivity. Mutations that have unexpected patterns of inheritance may represent allelic variability. Muscle Nerve 49:593–600, 2014     

Late‐onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2‐related diseases

Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot–Marie‐Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53‐year‐old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2‐related diseases. Sequencing of MFN2 should be considered in all patients presenting with late‐onset HSAN.