Atypical presentations in an RTD patient and report of novel SLC52A3 and SLC52A2 mutations.

INTRODUCTION: Riboflavin Transporter Deficiency (RTD) is a rare neurological disorder characterized by pontobulbar palsy, hearing loss, and motor cranial nerve involvement. SLC52A3 and SLC52A2 mutations are causes of RTD. SLC52A2 mutations are usually found in childhood onset cases. Fifteen Iranian RTD diagnosed patients without SLC52A2 mutations have been previously described. We aimed to identify causative mutations in two childhood cases. METHODS: We recruited patients with diagnosis of BVVL. Comprehensive clinical evaluations were performed on the patients. SLC52A3 and SLC52A2 genes were PCR-amplified and Sanger sequenced. Candidate disease causing variations were screened for segregation with disease status in the respective families and control individuals. RESULTS: A novel homozygous SLC52A3 mutation (p.Met1Val) and a heterozygous SLC52A2 mutation (p.Ala288Val) were both observed in one proband with typical RTD presentations. The aggregate of presentations in the early stages of disease in the second patient that included weakness in the lower extremities, absence of bulbar or hearing defects, prominent sensory polyneuropathy as evidenced in electrodiagnostic studies, and absence of sensory symptoms including sensory ataxia did not prompt immediate RTD diagnosis. Dysarthria and decreased hearing manifested later in the disease course. A novel homozygous SLC52A2 (p.Val314Met) mutation was identified. CONCLUSION: A literature search found recent reports of other atypical RTD presentations. These include MRI findings, speech understanding difficulties accompanied by normal hearing, anemia, and left ventricular non-compaction. Knowledge of unusual presentations lessens the chance of misdiagnosis or delayed RTD diagnosis which, in light of favorable effects of riboflavin supplementation, is of immense importance.

Towards a Global View of Parkinson's Disease Genetics.

Parkinson's disease (PD) is a global health challenge, yet historically studies of PD have taken place predominantly in European populations. Recent genetics research conducted in non-European populations has revealed novel population-specific genetic loci linked to PD risk, highlighting the importance of studying PD globally. These insights have broadened our understanding of PD etiology, which is crucial for developing disease-modifying interventions. This review comprehensively explores the global genetic landscape of PD, emphasizing the scientific rationale for studying underrepresented populations. It underscores challenges, such as genotype-phenotype heterogeneity and inclusion difficulties for non-European participants, emphasizing the ongoing need for diverse and inclusive research in PD. ANN NEUROL 2024;95:831-842.

Identification of a mutation in TNRC18 in a patient with clinical features of Fazio-Londe disease.

Fazio-Londe disease and Brown-Vialetto-Van Laere syndrome are rare related neurological disorders. Although SLC52A3 and SLC52A2 that encode riboflavin transporters are their only known causative genes, many patients without mutations in these genes have been reported. Clinical and genetic data of a patient with features suggestive of Fazio-Londe disease are presented. Neurological examination revealed significant involvement of cranial nerves and weakness in the lower extremities. Pontobulbar presentations were prominent. EDX study suggested motor neuronopathy. Hearing was normal. She was diagnosed with FL disease. Response to riboflavin supplementation was not favorable. The patient's pedigree suggested recessive inheritance. SLC52A3 and SLC52A2 were screened and mutations were not observed. Results of exome sequencing and segregation analysis suggested that a mutation in TNRC18 is a candidate cause of disease in the patient. The three dimensional structure of the TNRC18 protein was predicted and it was noted that its two conserved domains (BAH and Tudor) interact and that the valine residue affected by the mutation is positioned close to both domains. A mutation in TNRC18 is cautiously reported as the possible cause of FL disease in the patient. The finding warrants further inquiries on TNRC18 about which little is presently known.

Water uptake by gecko ß-keratin and the influence of relative humidity on its mechanical and volumetric properties.

Grand canonical ensemble molecular dynamics simulations are done to calculate the water content of gecko ß-keratin as a function of relative humidity (RH). For comparison, we experimentally measured the water uptake of scales of the skin of cobra Naja nigricollis. The calculated sigmoidal sorption isotherm is in good agreement with experiment. To examine the softening effect of water on gecko keratin, we have calculated the mechanical properties of dry and wet keratin samples, and we have established relations between the mechanical properties and the RH. We found that a higher RH causes a decrease in the Young's modulus, the yield stress, the yield strain, the stress at failure and an increase in the strain at failure of the gecko keratin. At low RHs (less than 80%), the change in the mechanical properties is small, with most of the changes occurring at higher RHs. The changes in the macroscopic properties of the keratin are explained by the action of sorbed water on the molecular scale. It causes keratin to swell, thereby increasing the distances between amino acids. This has a weakening effect on amino acid interactions and softens the keratin material. The effect is more pronounced at higher RHs.

Identification of UBA1 as the causative gene of an X-linked non-Kennedy spinal-bulbar muscular atrophy.

BACKGROUND AND PURPOSE: Spinal-bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (AR). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in AR are reported. METHODS: Clinical investigations included thorough neurological and non-neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. UBA1 mutations were modeled on the crystal structure of UBA1. RESULTS: The clinical features of the patients are described in detail. A missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non-Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin-like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin-proteasome system. Interestingly, UBA1 mutations can also cause infantile-onset X-linked spinal muscular atrophy (XL-SMA). The mutation identified here and the XL-SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes. CONCLUSION: UBA1 was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL-SMA is discussed.

Identification of RNF13 as cause of recessively inherited ALS in a multi-case pedigree.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. The approximately 50 known ALS-associated genes do not fully explain its heritability, which suggests the existence of yet unidentified causative genes. We report results of studies aimed at identification of the genetic cause of ALS in a pedigree (three patients) without mutations in the common ALS-causative genes. METHODS: Clinical investigations included thorough neurological and non-neurological examinations and testings. Genetic analysis was performed by exome sequencing. Functional studies included identification of altered splicing by PCR and sequencing, and mutated proteins by western blot analysis. Apoptosis in the presence and absence of tunicamycin was assessed in transfected HEK293T cells using an Annexin-PE-7AAD kit in conjunction with flow cytometry. RESULTS: Clinical features are described in detail. Disease progression in the patients of the pedigree was relatively slow and survival was relatively long. An RNF13 mutation was identified as the cause of the recessively inherited ALS in the pedigree. The gene is highly conserved, and its encoded protein (RING finger protein 13) can potentially affect various neurodegenerative-relevant functions, including protein homeostasis. The RNF13 splice site mutation caused expression of two mis-spliced forms of RNF13 mRNA and an aberrant RNF13 protein, and affected apoptosis. CONCLUSION: RNF13 was identified as a novel causative gene of recessively inherited ALS. The gene affects protein homeostasis, which is one of most important components of the pathology of neurodegeneration. The contribution of RNF13 to the aetiology of another neurodegenerative disease is discussed.

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer's disease.

The search for rare variants in Alzheimer's disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful.Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs.Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aß pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions.Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs.

A case of adult onset Sandhoff disease that mimics Brown-Vialetto-Van Laere syndrome.

Sandhoff disease is a rare fatal infantile neurologic disorder. Adult onset Sandhoff is even rarer. Variability of clinical features in adult onset Sandhoff patients and overlaps between these and features of other neurologic diseases have sometimes led to mis-diagnosis. We describe an adult onset Sandhoff disease affected individual whose clinical presentation were also consistent with the Brown-Vialetto-Van Laere syndrome (BVVL) diagnosis. Screening of BVVL-causing genes, SLC52A3 and SLC52A2, did not identify candidate disease-causing mutations, but exome sequencing revealed compound heterozygous mutations in the known Sandhoff disease-causing gene, HEXB. Decreased blood hexosaminidase activity and evidence of cerebellar atrophy confirmed Sandhoff disease diagnosis. To the best of our knowledge, this is the first report of a Sandhoff disease case that mimics BVVL and that presents with prominent cranial nerve involvement. For differential diagnosis, measurement of hexosaminidase activity and MRI should quickly be performed. Genetic analysis can be done for confirmation of diagnosis.

Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a prevalent and heterogeneous peripheral neuropathy. Most patients affected with the axonal form of CMT (CMT2) do not harbor mutations in the approximately 90 known CMT-associated genes. We aimed to identify causative genes in two CMT2 pedigrees. METHODS: Neurologic examination, laboratory tests and brain MRIs were performed. Genetic analysis included exome sequencing of four patients from the two pedigrees. The predicted effect of a deep intronic mutation on splicing was tested by regular and real-time PCR and sequencing. RESULTS: Clinical data were consistent with CMT2 diagnosis. Inheritance patterns were autosomal recessive. Exome data of CMT2-101 did not include mutations in known CMT-associated genes. Sequence data, segregation analysis, bioinformatics analysis, evolutionary conservation, and information in the literature strongly implicated HADHA as the causative gene. An intronic variation positioned 23 nucleotides away from following intron/exon border in GDAP1 was ultimately identified as cause of CMT in CMT2-102. It was shown to affect splicing. CONCLUSION: The finding of a HADHA mutation as a cause of CMT is of interest because its encoded protein is a subunit of the mitochondrial trifunctional protein (MTP) complex, a mitochondrial enzyme involved in long chain fatty acid oxidation. Long chain fatty acid oxidation is an important source of energy for skeletal muscles. The mutation found in CMT2-102 is only the second intronic mutation reported in GDAP1. The mutation in the CMT2-102 pedigree was outside the canonical splice site sequences, emphasizing the importance of careful examination of available intronic sequences in exome sequence data.

BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes.

Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.

Insights into the regulatory molecules involved in glaucoma pathogenesis.

Glaucoma is an important cause of irreversible blindness, characterized by optic nerve anomalies. Increased intraocular pressure (IOP) and aging are major risk factors. Retinal ganglion cells and trabecular meshwork cells are certainly involved in the etiology of glaucoma. Glaucoma is usually a complex disease, and various genes and functions may contribute to its etiology. Among these may be genes that encode regulatory molecules. In this review, regulatory molecules including 18 transcription factors (TFs), 195 microRNAs (miRNAs), 106 long noncoding RNAs (lncRNAs), and two circular RNAs (circRNAs) that are reasonable candidates for having roles in glaucoma pathogenesis are described. The targets of the regulators are reported. Glaucoma-related features including apoptosis, stress responses, immune functions, ECM properties, IOP, and eye development are affected by the targeted genes. The targeted genes that are frequently targeted by multiple regulators most often affect apoptosis and the related features of cell death and cell survival. BCL2, CDKN1A, and TP53 are among the frequent targets of three types of glaucoma-relevant regulators, TFs, miRNAs, and lncRNAs. TP53 was itself identified as a glaucoma-relevant TF. Several of the glaucoma-relevant TFs are themselves among frequent targets of regulatory molecules, which is consistent with existence of a complex network involved in glaucoma pathogenesis.

Description of combined ARHSP/JALS phenotype in some patients with SPG11 mutations.

BACKGROUND: SPG11 mutations can cause autosomal recessive hereditary spastic paraplegia (ARHSP) and juvenile amyotrophic lateral sclerosis (JALS). Because these diseases share some clinical presentations and both can be caused by SPG11 mutations, it was considered that definitive diagnosis may not be straight forward. METHODS: The DNAs of referred ARHSP and JALS patients were exome sequenced. Clinical data of patients with SPG11 mutations were gathered by interviews and neurological examinations including electrodiagnosis (EDX) and magnetic resonance imaging (MRI). RESULTS: Eight probands with SPG11 mutations were identified. Two mutations are novel. Among seven Iranian probands, six carried the p.Glu1026Argfs*4-causing mutation. All eight patients had features known to be present in both ARHSP and JALS. Additionally and surprisingly, presence of both thin corpus callosum (TCC) on MRI and motor neuronopathy were also observed in seven patients. These presentations are, respectively, key suggestive features of ARHSP and JALS. CONCLUSION: We suggest that rather than ARHSP or JALS, combined ARHSP/JALS is the appropriate description of seven patients studied. Criteria for ARHSP, JALS, and combined ARHSP/JALS designations among patients with SPG11 mutations are suggested. The importance of performing both EDX and MRI is emphasized. Initial screening for p.Glu1026Argfs*4 may facilitate SPG11 screenings in Iranian patients.

Observation of nine previously reported and 10 non-reported SLC4A11 mutations among 20 Iranian CHED probands and identification of an MPDZ mutation as possible cause of CHED and FECD in one family.

BACKGROUND/AIMS: SLC4A11 is the only known causative gene of congenital hereditary endothelial dystrophy (CHED). Mutation screenings have shown that most but not all patients with CHED harbour mutations in SLC4A11, suggesting that other CHED-causing genes may exist. We aimed to screen SLC4A11 in Iranian patients to learn the mutation spectrum of this gene among Iranians and to gain further knowledge on potential contribution of other genes to CHED aetiology. METHODS: SLC4A11 was screened in 21 Iranian patients with CHED by sequencing. Previously unreported variations were checked in at least 200 controls, and segregation analysis within families and bioinformatics predictions on effects of variations were performed. Exome sequencing was done for the single patient without an SLC4A11 mutation and for her parents. RESULTS: Nine previously reported and 10 unreported SLC4A11 mutations were observed among 20 patients; a mutation was not found in one patient. A mutation in MPDZ was identified as the only candidate cause of CHED in this patient. Her mother who carried the same mutation was diagnosed with Fuchs endothelial corneal dystrophy (FECD). CONCLUSION: SLC4A11 mutations are the usual cause of CHED in Iranians. The 10 novel mutations observed contribute significantly to the approximately 85 mutations reported since discovery of the role of the gene in CHED pathogenesis more than 10 years ago. MPDZ mutations may be a cause of CHED and even FECD in a minority of patients. Proposed functions of MPDZ with respect to tight junctions and maintenance of the corneal endothelial barrier are in accordance with a role in corneal endothelial pathobiology.

Continuum of phenotypes in hereditary motor and sensory neuropathy with proximal predominance and Charcot-Marie-Tooth patients with TFG mutation.

Charcot-Marie-Tooth (CMT) is a common neuropathy, and hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a recently described rare neuromuscular disease. Although many genes have been implicated for CMT, TFG is the only known HMSN-P-causing gene. Within the framework of diagnostic criteria, clinical variation is evident among CMT-diagnosed and also HMSN-P-diagnosed individuals. Mutations that cause p.(Pro285Leu) and p.(Gly269Val) in TFG were earlier reported as cause of HMSN-P in two Iranian pedigrees. Here, we report the identification of p.(Gly269Val) in TFG as cause of CMT in a large Iranian pedigree. The clinical features of patients of the three pedigrees are presented and critically compared. Similarities between the two HMSN-P-diagnosed pedigrees with different TFG mutations, and differences between the two differentially diagnosed pedigrees with the same p.(Gly269Val) mutation were evident. The clinical features of the HMSN-P pedigree with the p.(Pro285Leu) and the CMT pedigree with the p.(Gly269Val) mutation were clearly congruent with the respective diagnoses, whereas the features of the HMSN-P-diagnosed pedigree with the p.(Gly269Val) were intermediate between the other two pedigrees. It is therefore suggested that the clinical features of the three Iranian pedigrees with TFG mutations and diagnosed with HMSN-P or CMT represent a continuum.

Gaussian Charge Distributions for Incorporation of Electrostatic Interactions in Dissipative Particle Dynamics: Application to Self-Assembly of Surfactants.

The point charges are distributed over the soft dissipative particle dynamics (DPD) beads using a Gaussian of tunable width. Screening the Gaussian smeared charge distributions, with wider Gaussians of opposite charge, splits the electrostatic interaction into the real- and the reciprocal-space contributions. This method is validated against model test systems in the literature. The method has also been employed to study self-assembly in solutions of sodium dodecyl sulfate (SDS) in water. The critical micelle concentration (CMC) and the equilibrium concentration of free surfactants, in solutions with SDS concentrations varying from CMC to ≈20 times larger than CMC, are in close agreement with experiment. The microscopic structure of the micelles and the distributions of its hydrophobic/hydrophilic groups and counterions at the water interface are in agreement with experiment. The dynamics of monomer exchange between micelles and solution is examined in terms of the intermittent and continuous correlation functions for the fluctuation of micelle size with time. Two discrete relaxation processes, whose relaxation times differ by 2 orders of magnitude are found. Using the natural DPD time unit, defined in terms of thermal velocity, the relaxation times are an order of magnitude shorter than experimental relaxation times for monomer exchange and establishment of equilibrium between surfactants in the solution and micelles through diffusion of surfactants. However, experimentally comparable relaxation times are obtained by defining the DPD time scale such that the calculated diffusion coefficient of water corresponds to its experimental value.

Mutation screening of SLC52A3, C19orf12, and TARDBP in Iranian ALS patients.

Mutations in the same gene are sometimes the cause of different clinically diagnosed neurologic disorders; this emphasizes interrelationships between various neurologic diseases. In this light, we screened SLC52A3, which is the cause of Brown-Vialetto-Van Laere syndrome, and C19orf12, which is the cause of neurodegeneration with brain iron accumulation in 60 Iranian amyotrophic lateral sclerosis (ALS) patients without mutations in the 2 most important ALS-causing genes, SOD1 and C9orf72. To the best of our knowledge, neither SLC52A3 nor C19orf12 has been mutation-screened previously in ALS cohorts. Justification for screening SLC52A3 included notable clinical similarities between Brown-Vialetto-Van Laere syndrome and ALS, and justification for screening C19orf12 was known contribution of mitochondrial dysfunction to ALS etiology. Disease-causing variations in the 2 genes were not found among the ALS patients. TARDBP was screened in 107 patients, and a mutation (p.Gly348Cys) was identified in one. Detailed clinical data on the patient are presented. It appears that mutations in TARDBP in ALS patients of Iran are rare and occur at similar frequencies to European populations.

Identification of direct target genes of miR-7, miR-9, miR-96, and miR-182 in the human breast cancer cell lines MCF-7 and MDA-MB-231.

Some microRNAs have carcinogenic or tumor suppressive effects in breast cancer, which is the most common cancer in women worldwide. MiR-7 and miR-9 are tumor suppressor microRNAs, which induce apoptosis and inhibit proliferation in breast cancer cells. Moreover, miR-96 and miR-182 are onco-microRNAs that increase proliferation, migration, and tumorigenesis in breast cancer cells. This study aimed to identify the direct target genes of these four microRNAs in the human breast cancer cell lines MCF-7 and MDA-MB-231. Initially, bioinformatics tools were used to identify the target genes that have binding sites for miR-7, MiR-9, MiR-96, and miR-182 and are also associated with breast cancer. Subsequently, the findings of the bioinformatics analysis relating to the effects of these four microRNAs on the 3'-UTR activity of the potential target genes were confirmed using the dual luciferase assay in MCF-7 and MDA-MB-231 cells co-transfected with the vectors containing 3'-UTR segments of the target genes downstream of a luciferase coding gene and each of the microRNAs. Finally, the effects of microRNAs on the endogenous expression of potential target genes were assessed by the overexpression of each of the four microRNAs in MCF-7 and MDA-MB-231 cells. Respectively, three, three, three, and seven genes were found to have binding sites for miR-7, miR-9, miR-96, and miR-182 and were associated with breast cancer. The results of empirical studies including dual luciferase assays and real-time PCR confirmed that miR-7 regulates the expression of BRCA1 and LASP1; MiR-9 regulates the expression of AR; miR-96 regulates the expression of ABCA1; and miR-182 regulates the expression of NBN, TOX3, and LASP1. Taken together, our results suggest that the tumor suppressive effects of miR-7 may be mediated partly by regulating the expression of BRCA1 as a tumor suppressor gene in breast cancer. In addition, this microRNA and miR-182 may have effects on the nodal-positivity and tumor size of breast carcinoma through the regulation of LASP1. The tumor suppressive functions of miR-9 may be mediated partly by suppressing the expression of AR-an oncogene in breast cancer. Moreover, miR-96 may play an oncogenic role in breast cancer by suppressing the apoptosis through the regulation of ABCA1.

Identification of novel TFG mutation in HMSN-P pedigree: Emphasis on variable clinical presentations.

We aimed to identify the genetic cause of neurological disease in an Iranian pedigree whose manifestations suggested hereditary motor and sensory neuropathy with proximal predominance (HMSN-P). Identification of a p.Gly269Val mutation in TFG, the known HMSN-P causative gene, provided supportive evidence. Subjective, biochemical, electrodiagnostic, and imaging data were compared with previously reported HMSN-P patients, including patients of an earlier described Iranian pedigree. Although notable clinical variability was found, comparable involvement of proximal and distal muscles was observed in both Iranian pedigrees. Interestingly, the same p.Gly269Val mutation was recently reported as cause of Charcot-Marie-Tooth disease type 2 in a Taiwanese pedigree. The likelihood that the two pedigrees with the p.Gly269Val mutation are not affected with different diseases is discussed. Identification of a second Iranian HMSN-P pedigree further confirms that HMSN-P is not confined to the Far East. Furthermore, p.Pro285Leu that has been the only TFG mutation thus far reported in HMSN-P patients is not the only mutation that can cause the disease. It is emphasized HMSN-P is a neuronopathy.

Observation of c.260A > G mutation in superoxide dismutase 1 that causes p.Asn86Ser in Iranian amyotrophic lateral sclerosis patient and absence of genotype/phenotype correlation.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder in European populations. ALS can be sporadic ALS (SALS) or familial ALS (FALS). Among 20 known ALS genes, mutations in C9orf72 and superoxide dismutase 1 (SOD1) are the most common genetic causes of the disease. Whereas C9orf72 mutations are more common in Western populations, the contribution of SOD1 to ALS in Iran is more than C9orf72. At present, a clear genotype/phenotype correlation for ALS has not been identified. We aimed to perform mutation screening of SOD1 in a newly identified Iranian FALS patient and to assess whether a genotype/phenotype correlation for the identified mutation exists. METHODS: The five exons of SOD1 and flanking intronic sequences of a FALS proband were screened for mutations by direct sequencing. The clinical features of the proband were assessed by a neuromuscular specialist (SN). The phenotypic presentations were compared to previously reported patients with the same mutation. RESULTS: Heterozygous c.260A > G mutation in SOD1 that causes Asn86Ser was identified in the proband. Age at onset was 34 years and site of the first presentation was in the lower extremities. Comparisons of clinical features of different ALS patients with the same mutation evidenced variable presentations. CONCLUSION: The c.260A > G mutation in SOD1 that causes Asn86Ser appears to cause ALS with variable clinical presentations.