DNM1L encodes dynamin-related protein 1 (DRP1), a multi-domain GTPase essential for mitochondrial... more DNM1L encodes dynamin-related protein 1 (DRP1), a multi-domain GTPase essential for mitochondrial and peroxisomal division. Autosomal dominant and recessive variants in DNM1L cause encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1), which presents as a complex and clinically heterogeneous neurological disorder of variable severity, often accompanied by seizures. Clinical features are diverse, and no clear phenotype-genotype correlations were drawn to date. DNM1L-related sensory neuropathy has recently been reported as a predominant feature in one case with a de novo variant in the GTPase domain. Herein we present a second case with DNM1L-related sensory neuropathy as the predominant underlying feature without motor neuron involvement, which resulted in severe muscular atrophy and generalized dystonia.
Here, we report two siblings with compound heterozygous variants in VPS13D but a considerable div... more Here, we report two siblings with compound heterozygous variants in VPS13D but a considerable divergent phenotype highlighting the difficulties of phenotype-genotype correlation in this rare disease. A 19-year-old patient presented to our outpatient department with a five-year history of progressive gait impairment. Motor and cognitive development during childhood was described as normal. The patient visited a regular school and was able to participate in physical education until the onset of symptoms. There were no known neurologic diseases in the Caucasian family, consisting of five sisters (II.1-3, II.5, and II.6), and the patient (II.4). However, one younger sister (II.6) of the patient suffered from developmental delay and intellectual disability without further physical impairment, and the oldest sister (II.1) living separate from the family was supposed to have "gait problems". On examination, the patient presented with saccadic pursuit, gaze-evoked nystagmus, and mild hypophonia, accompanied by mild dysmetria of the lower limbs, spastic tetraparesis pronounced in the lower limbs (MRC 4), and a spastic ataxic gait with footdrop on the left (see Table 1 and Video 1). Video 1. Clinical examination of the patients (II.4 and II.6) including smooth pursuit, speech, test for dysmetria, fast finger movement, and gait.
Hereditary lower motor neuron diseases (LMND) other than 5q‐spinal muscular atrophy (5q‐SMA) can ... more Hereditary lower motor neuron diseases (LMND) other than 5q‐spinal muscular atrophy (5q‐SMA) can be classified according to affected muscle groups. Proximal and distal forms of non‐5q‐SMA represent a clinically and genetically heterogeneous spectrum characterized by significant overlaps with axonal forms of Charcot–Marie–Tooth (CMT) disease. A consensus for the best approach to molecular diagnosis needs to be reached, especially in light of continuous novel gene discovery and falling costs of next‐generation sequencing (NGS). We performed exome sequencing (ES) in 41 families presenting with non‐5q‐SMA or axonal CMT, 25 of which had undergone a previous negative neuromuscular disease (NMD) gene panel analysis. The total diagnostic yield of ES was 41%. Diagnostic success in the cohort with a previous NMD‐panel analysis was significantly extended by ES, primarily due to novel gene associated‐phenotypes and uncharacteristic phenotypic presentations. We recommend early ES for individuals...
The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans a... more The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozy...
Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are ... more Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2. Hereditary axonal neuropathies are a heterogenous group of disorders characterized by normal or moderately reduced nerve conduction velocities. 1 Classically, they are classified into two subgroups depending on the affected fiber type. The distal hereditary motor neuropathies (HMNs) are characterized by pure motor neuropathy, whereas the axonal Charcot-Marie-Tooth neuropathy (CMT2) have both motor and sensory involvement. 1 The cardinal phenotype of these entities is a length-dependent motor neuropathy that predominantly affects the distal foot and peroneal muscles and results in foot abnormalities or deformities and gait disturbance. Clinically, HMNs/CMT2 present with extreme heterogeneity in terms of onset, clinical course, associated neurological features (i.e., sensory or cerebellar involvement), and other co-presenting signs, including seizures, fractures, and respiratory distress, among others. 2-4 This variability not only results in complex phenotypic categorizations but also in diagnostic challenges and potential misinterpretation of genetic findings. The integration of next-generation sequencing (NGS) technologies into routine genetic diagnostics and the ensuing yield of novel disease genes has greatly expanded the number of loci associated with axonal neuropathies. Notwithstanding that, a successful genetic diagnosis is possible only in about half of the individuals with HMN/ CMT2. 5,6 Variants in more than 60 genes have been associated with autosomal-dominant forms of HMN or CMT2, which are phenotypically very similar (see ''Muscle Gene Table'' and ''Inherited Neuropathy Variant Browser'' in Web Resources). These genes, although functionally heterogeneous, have revealed common molecular mechanisms underlying the pathology of dominant HMNs, such as protein misfolding and aggregation, 7-9 disrupted axonal transport, 9-12 and mitochondria dysfunction. 13-15 Over the past years, we, as well as others, have identified heterozygous variants in BICD cargo adaptor 2, also known as bicaudal D homolog 2 (Drosophila) (BICD2 [MIM: 609797]),
In the original version of this Article there was a nomenclature error in Table 2 and Supplementa... more In the original version of this Article there was a nomenclature error in Table 2 and Supplementary Table S1. For patient 30 it should read c.[2863C>T];[3082+1G>C] and not c.[2863C>T];[3082+1C>G]. This has now been corrected in both the PDF and HTML versions of the Article as well as the supplementary information file.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Giant axonal neuropathy (GAN) is a rare neurodegenerative disorder affecting both the central and... more Giant axonal neuropathy (GAN) is a rare neurodegenerative disorder affecting both the central and peripheral nervous systems progressively. The recessive mutations of the GAN gene are responsible for the disease. Although some clinical aspects, like coarse and kinky hair, are suggestive, other diseases may interfere with diagnosis. We describe a case who previously had been diagnosed with and treated for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); after re-evaluation, genetic testing was received, and the patient was diagnosed with GAN.
Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic et... more Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. Methods: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). Results: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1,
Rare diseases are often misdiagnosed or receive a delayed diagnosis; thus, unfortunately, affecte... more Rare diseases are often misdiagnosed or receive a delayed diagnosis; thus, unfortunately, affected individuals may not receive optimal medical management. Here, we report a case of two siblings with a severe phenotype of progressive pseudorheumatoid dysplasia (PPD). Their onset of symptoms began at the age of 3 yr. Both were neglected in the past, and the patients presented with a very severe phenotype and unmitigated natural history. PPD is a rare autosomal recessive skeletal dysplasia characterized by progressive joint stiffness, swelling, and pain. Because of observed muscle wasting, weakness, and the lack of laboratory testing, the case had been initially misdiagnosed by the local physicians. We aimed to provide diagnostic support by a targeted next-generation sequencing gene panel (Illumina TruSight One) for Mendelian diseases (Mendeliome), and we identified a homozygous frameshift mutation in the gene WISP3 (c.868_869delAG, p.Ser290Leufs*12). Thus, early diagnosis and interven...
ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to ce... more ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation....
Spinal muscular atrophies (SMA) is a heterogeneous group of disorders characterized by muscular a... more Spinal muscular atrophies (SMA) is a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48% carried a homozygous SMN1 deletion, 2.8% a subtle mutation and an SMN1 deletion while 49.2% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analysed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel en...
Introduction Biologically active forms of riboflavin, which is an important factor in myelin synt... more Introduction Biologically active forms of riboflavin, which is an important factor in myelin synthesis, are important cofactors of carbohydrate, amino acid, and lipid metabolism. The mutations in the riboflavin transporter genes (SLC52A2, SLC52A3) cause riboflavin transporter deficiency (Brown-Vialetto-Van Laere syndrome, BVVLS). BVVLS is a rare neurodegenerative disease that can be treated. Herein, a premature infant, who has signs of hypotonia and right diaphragmatic eventration, and pre-diagnosed spinal muscular atrophy with respiratory distress (SMARD) syndrome, however; patient’s genetic analysis revealed autosomal recessively inherited riboflavin transporter deficiency, is presented. Case A girl infant, referred to our unit at the second day, was born 2400 g at 33rd week from a consanguineous marriage. Apgar score was 5/7 at 1st and 5th minute and she was intubated due to irregular respiration and hypotonia. The history of the patient revealed that the pregnancy was normal and her first brother diagnosed with hypotonic infant and died when he was six months old. Physical examination showed paradoxical respiration, severe hypotonia, decreased deep-tendon reflexes, generalised muscle weakness. Right diaphragmatic eventration was shown on her chest x-ray. Biochemical evaluations, creatine kinase, blood gas, lactate, pyruvate, ammonia, urine-blood amino acids and urine organic acid analysis were normal. Tandem-MS revealed high levels of C5 and C6. SMN1 gene deletion was not detected, so, diagnosis of SMA was excluded. Auditory brainstem response test was normal. The patient was considered as SMARD due to hypotonia and diaphragmatic eventration. A neuromuscular panel which screens 443 neuromuscular disease genes was tested for genetic diagnosis. The patient was extubated when she was 80 days old. She was discharged with enteral tube feeding when she was 110 days old. The patient was diagnosed with BVVLS with mutations in the SLC52A2 gene (c.-110–1G> A, c.297G> C). Oral riboflavin was initiated at the dose of 10–40 mg/kg/day to the patient. Spontaneous movements in the patient’s lower limbs started and swallowing dysfunction regressed with the therapy of riboflavin. She is still under clinical following-up. Conclusion If it could not be diagnosed in hypotonic infants performed to primary investigations, molecular genetic analyses should be kept in mind to diagnosis for rare neuromuscular diseases such as riboflavin transporter deficiency.
Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases of the neuromuscular ... more Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases of the neuromuscular junction caused by compromised synaptic transmission. Clinical features include early-onset weakness of limbs and oculobulbar muscles resulting in hypotonia, bulbar paresis, ptosis, and hypoventilation. The first dropped head syndrome in children were detected in 2 patients with LMNA and SEPN1 mutations. We report a 17-month-old boy with dropped head and limb-girdle weakness, who had no ptosis or ophthalmoplegia at presentation. We performed whole exome sequencing, which revealed a homozygous missense variant in the AGRN gene c.5023G>A, p.Gly1675Ser in the LG2 domain, which is predicted to be likely disease causing by in silico tools. Agrin is known to play a critical role in the development and maintenance of the neuromuscular junction. Agrin-related CMS is one of the rarest subtypes. Of note, our patient is the first described patient with agrin-related CMS with dropped head phenotype.
Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of dis... more Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of disorders. Mostly myopathic and neurogenic defects have been described, but many patients remain without genetic diagnosis. We are elaborating on the clinical presentation of neonatal cases with DA who carry novel mutations in the nonselective sodium leak channel (NALCN). Two patients reported herein were remarkable for central hypertonicity in addition to DA. By trio-whole exome sequencing, two undescribed de novo mutations in NALCN were revealed. Both mutations (p.F317C and p.V595F) are located on pore-forming segments of NALCN. Dominant NALCN mutations in the pore-forming segments have been identified in similar patients, whereas recessive mutations outside the pore-forming segments result in different phenotypes. Our findings with central hypertonia broaden the phenotypic spectrum of de novo mutations in the pore-forming segments of NALCN. Recent findings of successful acetazolamide treatment in patients with channelopathies might point to potential therapies based on the ion channel similarities and the location of the mutation.
Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotoni... more Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK) levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES) after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB) gene c.1031G>A (p.R344Q) in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystro...
Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of ne... more Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to a...
DNM1L encodes dynamin-related protein 1 (DRP1), a multi-domain GTPase essential for mitochondrial... more DNM1L encodes dynamin-related protein 1 (DRP1), a multi-domain GTPase essential for mitochondrial and peroxisomal division. Autosomal dominant and recessive variants in DNM1L cause encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1), which presents as a complex and clinically heterogeneous neurological disorder of variable severity, often accompanied by seizures. Clinical features are diverse, and no clear phenotype-genotype correlations were drawn to date. DNM1L-related sensory neuropathy has recently been reported as a predominant feature in one case with a de novo variant in the GTPase domain. Herein we present a second case with DNM1L-related sensory neuropathy as the predominant underlying feature without motor neuron involvement, which resulted in severe muscular atrophy and generalized dystonia.
Here, we report two siblings with compound heterozygous variants in VPS13D but a considerable div... more Here, we report two siblings with compound heterozygous variants in VPS13D but a considerable divergent phenotype highlighting the difficulties of phenotype-genotype correlation in this rare disease. A 19-year-old patient presented to our outpatient department with a five-year history of progressive gait impairment. Motor and cognitive development during childhood was described as normal. The patient visited a regular school and was able to participate in physical education until the onset of symptoms. There were no known neurologic diseases in the Caucasian family, consisting of five sisters (II.1-3, II.5, and II.6), and the patient (II.4). However, one younger sister (II.6) of the patient suffered from developmental delay and intellectual disability without further physical impairment, and the oldest sister (II.1) living separate from the family was supposed to have "gait problems". On examination, the patient presented with saccadic pursuit, gaze-evoked nystagmus, and mild hypophonia, accompanied by mild dysmetria of the lower limbs, spastic tetraparesis pronounced in the lower limbs (MRC 4), and a spastic ataxic gait with footdrop on the left (see Table 1 and Video 1). Video 1. Clinical examination of the patients (II.4 and II.6) including smooth pursuit, speech, test for dysmetria, fast finger movement, and gait.
Hereditary lower motor neuron diseases (LMND) other than 5q‐spinal muscular atrophy (5q‐SMA) can ... more Hereditary lower motor neuron diseases (LMND) other than 5q‐spinal muscular atrophy (5q‐SMA) can be classified according to affected muscle groups. Proximal and distal forms of non‐5q‐SMA represent a clinically and genetically heterogeneous spectrum characterized by significant overlaps with axonal forms of Charcot–Marie–Tooth (CMT) disease. A consensus for the best approach to molecular diagnosis needs to be reached, especially in light of continuous novel gene discovery and falling costs of next‐generation sequencing (NGS). We performed exome sequencing (ES) in 41 families presenting with non‐5q‐SMA or axonal CMT, 25 of which had undergone a previous negative neuromuscular disease (NMD) gene panel analysis. The total diagnostic yield of ES was 41%. Diagnostic success in the cohort with a previous NMD‐panel analysis was significantly extended by ES, primarily due to novel gene associated‐phenotypes and uncharacteristic phenotypic presentations. We recommend early ES for individuals...
The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans a... more The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozy...
Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are ... more Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2. Hereditary axonal neuropathies are a heterogenous group of disorders characterized by normal or moderately reduced nerve conduction velocities. 1 Classically, they are classified into two subgroups depending on the affected fiber type. The distal hereditary motor neuropathies (HMNs) are characterized by pure motor neuropathy, whereas the axonal Charcot-Marie-Tooth neuropathy (CMT2) have both motor and sensory involvement. 1 The cardinal phenotype of these entities is a length-dependent motor neuropathy that predominantly affects the distal foot and peroneal muscles and results in foot abnormalities or deformities and gait disturbance. Clinically, HMNs/CMT2 present with extreme heterogeneity in terms of onset, clinical course, associated neurological features (i.e., sensory or cerebellar involvement), and other co-presenting signs, including seizures, fractures, and respiratory distress, among others. 2-4 This variability not only results in complex phenotypic categorizations but also in diagnostic challenges and potential misinterpretation of genetic findings. The integration of next-generation sequencing (NGS) technologies into routine genetic diagnostics and the ensuing yield of novel disease genes has greatly expanded the number of loci associated with axonal neuropathies. Notwithstanding that, a successful genetic diagnosis is possible only in about half of the individuals with HMN/ CMT2. 5,6 Variants in more than 60 genes have been associated with autosomal-dominant forms of HMN or CMT2, which are phenotypically very similar (see ''Muscle Gene Table'' and ''Inherited Neuropathy Variant Browser'' in Web Resources). These genes, although functionally heterogeneous, have revealed common molecular mechanisms underlying the pathology of dominant HMNs, such as protein misfolding and aggregation, 7-9 disrupted axonal transport, 9-12 and mitochondria dysfunction. 13-15 Over the past years, we, as well as others, have identified heterozygous variants in BICD cargo adaptor 2, also known as bicaudal D homolog 2 (Drosophila) (BICD2 [MIM: 609797]),
In the original version of this Article there was a nomenclature error in Table 2 and Supplementa... more In the original version of this Article there was a nomenclature error in Table 2 and Supplementary Table S1. For patient 30 it should read c.[2863C>T];[3082+1G>C] and not c.[2863C>T];[3082+1C>G]. This has now been corrected in both the PDF and HTML versions of the Article as well as the supplementary information file.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Giant axonal neuropathy (GAN) is a rare neurodegenerative disorder affecting both the central and... more Giant axonal neuropathy (GAN) is a rare neurodegenerative disorder affecting both the central and peripheral nervous systems progressively. The recessive mutations of the GAN gene are responsible for the disease. Although some clinical aspects, like coarse and kinky hair, are suggestive, other diseases may interfere with diagnosis. We describe a case who previously had been diagnosed with and treated for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); after re-evaluation, genetic testing was received, and the patient was diagnosed with GAN.
Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic et... more Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. Methods: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). Results: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1,
Rare diseases are often misdiagnosed or receive a delayed diagnosis; thus, unfortunately, affecte... more Rare diseases are often misdiagnosed or receive a delayed diagnosis; thus, unfortunately, affected individuals may not receive optimal medical management. Here, we report a case of two siblings with a severe phenotype of progressive pseudorheumatoid dysplasia (PPD). Their onset of symptoms began at the age of 3 yr. Both were neglected in the past, and the patients presented with a very severe phenotype and unmitigated natural history. PPD is a rare autosomal recessive skeletal dysplasia characterized by progressive joint stiffness, swelling, and pain. Because of observed muscle wasting, weakness, and the lack of laboratory testing, the case had been initially misdiagnosed by the local physicians. We aimed to provide diagnostic support by a targeted next-generation sequencing gene panel (Illumina TruSight One) for Mendelian diseases (Mendeliome), and we identified a homozygous frameshift mutation in the gene WISP3 (c.868_869delAG, p.Ser290Leufs*12). Thus, early diagnosis and interven...
ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to ce... more ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation....
Spinal muscular atrophies (SMA) is a heterogeneous group of disorders characterized by muscular a... more Spinal muscular atrophies (SMA) is a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48% carried a homozygous SMN1 deletion, 2.8% a subtle mutation and an SMN1 deletion while 49.2% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analysed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel en...
Introduction Biologically active forms of riboflavin, which is an important factor in myelin synt... more Introduction Biologically active forms of riboflavin, which is an important factor in myelin synthesis, are important cofactors of carbohydrate, amino acid, and lipid metabolism. The mutations in the riboflavin transporter genes (SLC52A2, SLC52A3) cause riboflavin transporter deficiency (Brown-Vialetto-Van Laere syndrome, BVVLS). BVVLS is a rare neurodegenerative disease that can be treated. Herein, a premature infant, who has signs of hypotonia and right diaphragmatic eventration, and pre-diagnosed spinal muscular atrophy with respiratory distress (SMARD) syndrome, however; patient’s genetic analysis revealed autosomal recessively inherited riboflavin transporter deficiency, is presented. Case A girl infant, referred to our unit at the second day, was born 2400 g at 33rd week from a consanguineous marriage. Apgar score was 5/7 at 1st and 5th minute and she was intubated due to irregular respiration and hypotonia. The history of the patient revealed that the pregnancy was normal and her first brother diagnosed with hypotonic infant and died when he was six months old. Physical examination showed paradoxical respiration, severe hypotonia, decreased deep-tendon reflexes, generalised muscle weakness. Right diaphragmatic eventration was shown on her chest x-ray. Biochemical evaluations, creatine kinase, blood gas, lactate, pyruvate, ammonia, urine-blood amino acids and urine organic acid analysis were normal. Tandem-MS revealed high levels of C5 and C6. SMN1 gene deletion was not detected, so, diagnosis of SMA was excluded. Auditory brainstem response test was normal. The patient was considered as SMARD due to hypotonia and diaphragmatic eventration. A neuromuscular panel which screens 443 neuromuscular disease genes was tested for genetic diagnosis. The patient was extubated when she was 80 days old. She was discharged with enteral tube feeding when she was 110 days old. The patient was diagnosed with BVVLS with mutations in the SLC52A2 gene (c.-110–1G> A, c.297G> C). Oral riboflavin was initiated at the dose of 10–40 mg/kg/day to the patient. Spontaneous movements in the patient’s lower limbs started and swallowing dysfunction regressed with the therapy of riboflavin. She is still under clinical following-up. Conclusion If it could not be diagnosed in hypotonic infants performed to primary investigations, molecular genetic analyses should be kept in mind to diagnosis for rare neuromuscular diseases such as riboflavin transporter deficiency.
Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases of the neuromuscular ... more Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases of the neuromuscular junction caused by compromised synaptic transmission. Clinical features include early-onset weakness of limbs and oculobulbar muscles resulting in hypotonia, bulbar paresis, ptosis, and hypoventilation. The first dropped head syndrome in children were detected in 2 patients with LMNA and SEPN1 mutations. We report a 17-month-old boy with dropped head and limb-girdle weakness, who had no ptosis or ophthalmoplegia at presentation. We performed whole exome sequencing, which revealed a homozygous missense variant in the AGRN gene c.5023G>A, p.Gly1675Ser in the LG2 domain, which is predicted to be likely disease causing by in silico tools. Agrin is known to play a critical role in the development and maintenance of the neuromuscular junction. Agrin-related CMS is one of the rarest subtypes. Of note, our patient is the first described patient with agrin-related CMS with dropped head phenotype.
Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of dis... more Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of disorders. Mostly myopathic and neurogenic defects have been described, but many patients remain without genetic diagnosis. We are elaborating on the clinical presentation of neonatal cases with DA who carry novel mutations in the nonselective sodium leak channel (NALCN). Two patients reported herein were remarkable for central hypertonicity in addition to DA. By trio-whole exome sequencing, two undescribed de novo mutations in NALCN were revealed. Both mutations (p.F317C and p.V595F) are located on pore-forming segments of NALCN. Dominant NALCN mutations in the pore-forming segments have been identified in similar patients, whereas recessive mutations outside the pore-forming segments result in different phenotypes. Our findings with central hypertonia broaden the phenotypic spectrum of de novo mutations in the pore-forming segments of NALCN. Recent findings of successful acetazolamide treatment in patients with channelopathies might point to potential therapies based on the ion channel similarities and the location of the mutation.
Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotoni... more Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK) levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES) after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB) gene c.1031G>A (p.R344Q) in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystro...
Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of ne... more Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to a...
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