Family History Of Neurological Disease Research Articles

Assessment of Stx-1A gene polymorphism (rs1569061) in relation to the development of multiple sclerosis in Egyptian patients

Multiple sclerosis (MS) is a multifactorial polygenic disease; results from autoimmune and neurodegenerative processes which lead to multifocal lesions of the central nervous system. Axonal degeneration was found to be prominent in the inflammation period of MS and contribute to the progression of disability. Soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) complex plays a vital role in the release of neurotransmitter by synaptic vesicle fusion. Stx-1A protein (Stx-1A), a major component of the SNARE complex, is widely expressed in brain tissue. This study intended to evaluate the prevalence of the Stx-1A gene polymorphism (rs1569061) in the Egyptian population with MS and to investigate its association with various clinical factors. This study included 65 adult Egyptian MS patients and 35 age- and sex-matched normal control subjects. Diagnosis of MS was made by an experienced neurologist according to revised McDonald criteria. All Patients underwent full history taking, included Age of onset of MS, disease duration, disease course and degree of disability according to the Expanded Disability Status Scale (EDSS) and family history of neurological diseases. Stx-1A gene polymorphism (rs1569061) genotyping was performed by TaqMan assay based quantitative real time (qPCR) and verified by sanger sequencer. Genotype and allele frequencies of (rs1569061) did not differ significantly between case and control groups. No difference was detected when comparing the genotype frequency and the allele frequency to different disease parameters. Discrepancy of the minor allele frequency (MAF) of Stx-1A gene (rs1569061) between different populations was noted. In conclusion, our study in Stx-1A gene polymorphism (rs1569061) and MS showed that no difference between the patient and control as regards gene frequency and allele frequency. Predicting no association between the studied polymorphism and MS in the Egyptian population. However, discrepancy between different population was noted as regards the MAF for Stx-1A gene (rs1569061).

Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders

Objective In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. Methods During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. Results A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson’s disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. Conclusion Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.

THU289 Hemichorea-Hemiballismus Syndrome Secondary To Steroid Induced Hyperglycemia In A Nondiabetic

Abstract Disclosure: E. Krishnaraju: None. K.N. Patolia: None. U.A. Ogar: None. S. Karki: None. A.G. Olafimihan: None. Introduction: Hemichorea-Hemiballismus syndrome (HCHB) associated with nonketotic hyperglycemia is a rare cause of acute to subacute acquired chorea. The syndrome is usually characterized by unilateral choreiform movements, poorly controlled diabetes mellitus, and striatal abnormalities on an MRI of the brain. Clinical Case: This is a case of a 70-year-old man with a history of congestive heart failure, hypertension, remote ischemic stroke, asymptomatic Paget's disease of the bone, chronic kidney disease, and statin-induced necrotizing myositis. Five months before his presentation, the patient was initiated on prednisone for myositis. On presenting to the ED, he had near resolution of his limb weakness from myositis but complained of one month of right-sided continuous involuntary tremors involving the right upper limb, lower limb, and face that resolved during his sleep. There was no family history of neurologic disorders or any history to suggest medication or illicit drug-induced movement disorders. On examination, the patient had normal cognitive functions and vital signs. Neurologic examination was remarkable for quick interspersed moderate amplitude choreiform movements of the right hand, forearm, proximal arm muscles, and right leg. Laboratory results revealed hyperglycemia and a newly elevated Hemoglobin A1c of 8.5, which was normal the year before. Infectious, hematologic, thyroid disease, and Wilson's disease workups were negative. Cerebrospinal fluid (CSF) analysis was remarkable for elevated glucose and identical oligoclonal bands in the serum and CSF, possibly suggestive of a nonspecific chronic systemic inflammatory state. Autoantibodies for paraneoplastic syndromes and autoimmune diseases, including autoimmune encephalitis were negative. There was also no evidence of occult malignancy on CT imaging of the chest, abdomen, and pelvis. MRI/MRA was significant for new small foci of susceptibility artifact in the bilateral basal ganglia, left cerebellar hemisphere, and cerebellar vermis, likely from chronic microvascular changes. The constellation of hemichorea and new onset hyperglycemia in the setting of a largely nondiagnostic workup raises suspicion for HBHC syndrome. Previous studies have found classic T1-weighted MRI hyperintensities in the basal ganglia, but normal imaging does not rule out a diagnosis of diabetic striatopathy. The patient was eventually discharged with mild improvement of his chorea after starting insulin and risperidone. Unfortunately, he was lost to follow-up and unexpectedly died of an unclear cause soon after. Conclusion: Metabolic complications of diabetes can manifest in complex ways. Non-ketotic hyperglycemic HCHB due to diabetic striatopathy is a rarely reported entity that is commonly misdiagnosed. This case is a unique presentation in a non-diabetic patient with steroid-induced hyperglycemia. Presentation: Thursday, June 15, 2023

An Unsuspecting Recurrent Cryptogenic Stroke: A Case Report

Cerebral Autosomal Dominant Arteriopathy with Sub-Cortical Infarcts and Leukoencephalopathy (CADASIL) is a rare autosomal genetic disorder that affects the brain’s small vessels. It is recognized among the leading causes of stroke in the young.
 This is a case report of a 35-year-old female with underlying migraine with auras who presented with recurrent cryptogenic strokes. She presented no vascular risk factors or any family history of neurological disease. An investigation into her presentation leads us to a diagnosis of CADASIL following typical subcortical and deep white matter changes seen on her Magnetic Resonance Imaging (MRI).

De novo PSEN1 mutation (Pro436Gln) in a very early onset posterior variant of Alzheimer's disease is associated with pyramidal signs.

Alzheimer's disease (AD) is a common cause of dementia even in cases with very early onset, and implication of monogenic mutations in the PSEN1, PSEN2, and APP genes must be considered. Strong family history is the rule in autosomal dominant AD associated with mutations in these genes but, in rare cases, de novo mutations can occur. Case report of a sporadic AD case with onset in his twenties carrying the Pro436Gln mutation (exon 12, TM-9 region) in PSEN1. Comparison with a previously reported familial case carrying the same mutation. A 32 years old male consulted for a 10 years-long mild but slowly progressive learning difficulties, apathy and anxiety. There was no family history of neurologic diseases and both parents were cognitively preserved in their early 70s. The previous two years he had developed progressive visual disturbances including impaired reading, recognizing numbers, letters and faces and, more recently, he had experienced troubles with manual praxias. There were no specific complaints regarding episodic memory. Neuropsychological assessment showed severe visual agnosia and mild impairments in memory, speech, and executive functions. Neurologic examination showed brief distal myoclonus in upper limbs, markedly enhanced reflexes in lower limbs, as well as mild spasticiy. Blood tests, EEG, spinal MRI, and SSEP were normal. Brain MRI and FDG-PET revealed severe parieto-occipital atrophy/hypoperfusion (fig. 1-4). AD CSF biomarkers showed decrease in Ab1-42 and 1-42/1-40 ratio, increased pTau and normal total tau. Amyloid-PET was positive, identifying a high burden of amyloid plaques in posterior cortex. The pathogenic PSEN1 mutation was found in the patient but was absent in his parents. It is remarkable that the phenotype of the previously reported case with this mutation was almost identical as regards onset in the late twenties and associated pyramidalism. PSEN1 mutations should be considered in patients with sporadic very early onset dementia, as de novo mutations may occur. AD CSF biomarkers offer valuable diagnostic information in such cases. The specific mutation has a very strong impact in the clinical phenotype. Further, this case is another example that PSEN1 mutations affecting proline residues have the earliest age at onset.

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. To identify the genetic variants associated with juvenile ALS. In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. De novo variants present only in the index case and not in unaffected family members. Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Variable Effects of PD-Risk Associated SNPs and Variants in Parkinsonism-Associated Genes on Disease Phenotype in a Community-Based Cohort.

Genetic risk factors for Parkinson's disease (PD) risk and progression have been identified from genome-wide association studies (GWAS), as well as studies of familial forms of PD, implicating common variants at more than 90 loci and pathogenic or likely pathogenic variants at 16 loci. With the goal of understanding whether genetic variants at these PD-risk loci/genes differentially contribute to individual clinical phenotypic characteristics of PD, we used structured clinical documentation tools within the electronic medical record in an effort to provide a standardized and detailed clinical phenotypic characterization at the point of care in a cohort of 856 PD patients. We analyzed common SNPs identified in previous GWAS studies, as well as low-frequency and rare variants at parkinsonism-associated genes in the MDSgene database for their association with individual clinical characteristics and test scores at baseline assessment in our community-based PD patient cohort: age at onset, disease duration, Unified Parkinson's Disease Rating Scale I-VI, cognitive status, initial and baseline motor and non-motor symptoms, complications of levodopa therapy, comorbidities and family history of neurological disease with one or more than one affected family members. We find that in most cases an individual common PD-risk SNP identified in GWAS is associated with only a single clinical feature or test score, while gene-level tests assessing low-frequency and rare variants reveal genes associated in either a unique or partially overlapping manner with the different clinical features and test scores. Protein-protein interaction network analysis of the identified genes reveals that while some of these genes are members of already identified protein networks others are not. These findings indicate that genetic risk factors for PD differentially affect the phenotypic presentation and that genes associated with PD risk are also differentially associated with individual disease phenotypic characteristics at baseline. These findings raise the intriguing possibility that different SNPs/gene effects impact discrete phenotypic characteristics. Furthermore, they support the hypothesis that different gene and protein-protein interaction networks that underlie PD risk, the PD phenotype, and the neurodegenerative process leading to the disease phenotype, and point to the significance of the genetic background on disease phenotype.

Evaluation of the role of ischemia modified albumin in neonatal hypoxic-ischemic encephalopathy.

BackgroundBirth asphyxia is a leading cause of neonatal mortality. Ischemia-modified albumin (IMA) levels may have a predictive role in the identification and prevention of hypoxic disorders, as they increase in cases of ischemia of the liver, heart, brain, bowel, and kidney.PurposeThis study aimed to assess the value of IMA levels as a diagnostic marker for neonatal hypoxic-ischemic encephalopathy (HIE).MethodsSixty newborns who fulfilled 3 or more of the clinical and biochemical criteria and developed HIE as defined by Levene staging were included in our study as the asphyxia group. Neonates with congenital malformation, systemic infection, intrauterine growth retardation, low-birth weight, cardiac or hemolytic disease, family history of neurological diseases, congenital or perinatal infections, preeclampsia, diabetes, and renal diseases were excluded from the study. Sixty healthy neonates matched for gestational age and with no maternal history of illness, established respiration at birth, and an Apgar score ≥7 at 1 and 5 minutes were included as the control group. IMA was determined by double-antibody enzymelinked immunosorbent assay of a cord blood sample collected within 30 minutes after birth.ResultsCord blood IMA levels were higher in asphyxiated newborns than in controls (250.83±36.07 pmol/mL vs. 120.24±38.9 pmol/mL). Comparison of IMA levels by HIE stage revealed a highly significant difference among them (207.3±26.65, 259.28±11.68, 294.99±4.41 pmol/mL for mild, moderate, and severe, respectively). At a cutoff of 197.6 pmol/mL, the sensitivity was 84.5%, specificity was 86%, positive predictive value was 82.8%, negative predictive value was 88.3%, and area under the curve was 0.963 (P<0.001).Conclusion IMA levels can be a reliable marker for the early diagnosis of neonatal HIE and can be a predictor of injury severity.

Psychogenic pseudoptosis: Case report with review of literature

BackgroundConversion disorder or functional neurological disorder is a psychiatric condition in which the body’s emotional and psychological stressors are converted to physical symptoms that cannot be explained by a neurological or medical condition. Psychogenic pseudoptosis is a rare manifestation of conversion disorder that present a major challenge in terms of diagnosis and treatment. Case descriptionA 36-year-old woman presented with acquired left ptosis and longstanding generalized weakness. She denied any toxic substance exposure, insect bites, recent travel or family history of neurological disease. The neurological examination was normal except for an atypical left ptosis with eyebrow droop and inability to walk. However, electrophysiological investigations were normal. The presence of dissociative symptoms and the improvement after starting pharmacotherapy in combination with psychotherapy led to the diagnosis of conversion disorder. ConclusionAfter the exclusion of organic causes, the conversion disorder must be considered in the differential diagnosis of acquired ptosis, especially when accompanied by eyebrows droop sign and a suggestive psychological context.

Evaluation of the Incidence of Other Cranial Neuropathies in Patients With Postviral Olfactory Loss

Postviral olfactory loss is a common cause of olfactory impairment, affecting both quality of life as well as overall patient mortality. It is currently unclear why some patients are able to recover fully after a loss while others experience permanent deficit. There is a lack of research on the possible association between postviral olfactory loss and other cranial neuropathies. To evaluate the incidence of other cranial nerve deficits in patients with postviral olfactory loss and determine if there is an association with neurologic injury in this group. This study also sought to determine if other known risk factors were associated with postviral olfactory loss. A case-control study was conducted at a tertiary care rhinology clinic from January 2015 to January 2018 to review the incidence of cranial neuropathies in 2 groups of patients, those with postviral olfactory loss and those with chronic rhinosinusitis without olfactory loss used as a control group. The Stanford Translational Research Integrated Database Environment (STRIDE) system was used for patient identification and data extraction. Patients with a history of olfactory loss or chronic rhinosinusitis as well as incidence of cranial neuropathies were identified by using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes. This study reviewed incidence of postviral or idiopathic cranial neuropathies in both patient groups, while also evaluating for any difference in demographic characteristics, comorbidities, or other patient-related factors. There were 91 patients in the postviral olfactory loss group and 100 patients in the control group, which were age and sex matched as closely as possible. Of the 91 patients with postviral olfactory loss, mean (SD) age was 56.8 (15.3), and 58 (64%) were women; for the control group, the mean (SD) age was 57.5 (15.6) years, and 63 (63%) were women. Racial breakdown was similar across cases and controls, with white individuals making up 59% to 65%; Asian individuals, 20% to 24%; black individuals, approximately 3%; Hispanic individuals, approximately 1%; and the remaining patients being of other race/ethnicity. The incidence of other cranial neuropathies in the postviral olfactory loss group was 11% compared with 2% within the control group (odds ratio, 6.1; 95% CI, 1.3-28.4). The study also found 2 cases of multiple cranial neuropathies within a single patient within the olfactory group. Family history of neurologic disease was associated with more than 2-fold greater odds of cranial nerve deficit (odds ratio, 3.05; 95% CI, 0.59-15.68). Postviral olfactory loss appears to be associated with a higher incidence of other cranial neuropathies. It is possible that there is an inherent vulnerability to nerve damage or decreased ability for nerve recovery in patients who experience this disease process.

Idiopathic brain calcification in a patient with hereditary hemochromatosis

BackgroundDetection of brain-MRI T2/T2* gradient echo images (T2*GRE)-hypointensity can be compatible with iron accumulation and leads to a differential diagnosis work-up including neurodegeneration with brain iron accumulation (NBIA) and Wilson Disease. Idiopathic or secondary brain calcification can be also associated with neurological involvement and brain-MRI T2/T2*GRE-hypointensity. Hereditary hemochromatosis (HH), characterized by systemic iron loading, usually does not involve the CNS, and only sporadic cases of neurological abnormalities or brain-MRI T2/T2*GRE-hypointensity have been reported.Case presentationA 59-year-old man came to our observation after a diagnosis of HH carried out in another hospital 2 years before. First-level genetic test had revealed a homozygous HFE p.Cys282Tyr (C282Y) mutation compatible with the diagnosis of HFE-related HH, thus phlebotomy treatment was started. The patient had a history of metabolic syndrome, type-2 diabetes, autoimmune thyroiditis and severe chondrocalcinosis. Brain-MRI showed the presence of bilateral T2*GRE hypointensities within globus pallidus, substantia nigra, dentate nucleus and left pulvinar that were considered expression of cerebral siderosis. No neurological symptoms or family history of neurological disease were reported. Neurological examination revealed only mild right-sided hypokinetic-rigid syndrome. Vitamin D–PTH axis, measurements of serum ceruloplasmin and copper, and urinary copper were within the normal range. A brain computed tomography (CT) was performed to better characterize the suspected and unexplained brain iron accumulation. On the CT images, the hypointense regions in the brain MRI were hyperdense. DNA sequence analysis of genes associated with primary familial brain calcification and NBIA was negative.ConclusionsThis report highlights the importance of brain CT-scan in ambiguous cases of suspected cerebral siderosis, and suggests that HH patients with a severe phenotype, and likely associated with chondrocalcinosis, may display also brain calcifications. Further studies are needed to confirm this hypothesis. So far, we can speculate that iron and calcium homeostasis could be reciprocally connected within the basal ganglia.

Orthostatic Jaw Tremor, a Diagnostic Challenge for Neurologists

Jaw tremor is usually associated with tremor or other abnormal involuntary movements affecting additional body parts, but isolated jaw tremor is a rare clinical presentation. A 40-year-old man presented with history of paroxysmal jaw tremor for 3 years with no other neurological symptoms, psychiatric conditions, or a family history of neurological disorders. The tremor occurred only in the resting jaw position, with 10 episodes per day on an average, and lasted from 10 minutes to hours. It disappeared with any voluntary activation of the masseter muscle and did not change (in amplitude or frequency) with distraction maneuvers. The remainder of neurologic examination was unremarkable. The patient underwent extensive testing, including contrast-enhanced brain magnetic resonance imaging, blood tests and neuropsychiatric evaluation by two different neuropsychiatrists which failed to reveal the underlying cause. The needle electromyography examination revealed involuntary, intermittent, and synchronized muscular contractions in both masseter muscles, at a frequency of 13 to 14 Hz. No changes were discovered in the other muscles. He was treated with propranolol, primidone, valproic acid, diazepam, and amitriptyline, but the response was not significant. Injection of 25 units of botulinum toxin type A in the masseter muscle on both sides of the fac was effective five days after the injection. No adverse effects or masseter weakness were observed.

Domperidone-Related Acute Dystonia in a Young Child With Underlying Abnormal Electroencephalogram

Domperidone is the preferred treatment for vomiting and gastroesophageal reflux in pediatric population. It is known to have lesser side effects compared to metoclopramide and is rarely associated with extrapyramidal side effects. We report a case of acute dystonia in a 4-year-old girl that occurred after given two doses of domperidone. She initially presented to the emergency department for persistent vomiting and treated with syrup domperidone, ranitidine and oral rehydration salts. Approximately 24 h after last dose of oral domperidone, she developed five episodes of abnormal movement, i.e. stiffness over bilateral upper and lower limbs with eye staring to one direction without blinking. Each episode lasted for less than 10 s and patient did not lose consciousness. No history of head trauma or any family history of neurological diseases was documented. Patient was admitted for workup to rule out seizure. In ward, she developed another two brief episodes of similar presentations which resolved spontaneously without any treatment. No re-occurrence of similar episodes throughout the 3 days of hospitalization was noted. Computed tomography scan of brain confirmed no acute intracranial bleed or focal brain lesion. Electroencephalogram done during subsequent clinic follow-up noted some abnormal records due to increase in slow delta activity, but parents did not consent for magnetic resonance imaging. Patient remained well on biannual follow-up without any seizure or dystonia episode. Rare adverse event involving the central nervous system should be carefully evaluated although product label for domperidone did not mention precaution of use in patients with underlying cerebral abnormalities or epilepsy. Int J Clin Pediatr. 2020;9(2):55-58 doi: https://doi.org/10.14740/ijcp364

A Case of Probable Diclofenac-Induced Acute Meningism in a Healthy Adolescent

Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are the common analgesics used in children who experience mild to moderate pain. NSAIDs-related case of aseptic meningitis or meningism in healthy adolescent is relatively uncommon. We report a case of an 11-year-old boy with underlying bronchial asthma who had recent intake of three doses of diclofenac (50 mg), presented with signs and symptoms mimicking acute meningism. The boy initially presented to the emergency department after he experienced throbbing headache, dizziness, nausea and persistent vomiting for about 15 times per day for the past 2 days. He did not report presence of any auditory or visual hallucination; however, he claimed to have a bit of photophobia. Signs and symptoms occurred soon after the second dose of diclofenac. Besides, he was also taking oral antibiotic Augmentin for his left epididymo-orchitis problem and famotidine for prevention of gastritis prescribed by general practitioner. Vital signs were normal, and review of systems did not find any abnormality. Neurological assessment found no significant deficit, no cerebellar sign, negative Babinski test and no sign of meningism. Patient did not have frequent fall, head trauma or any family history of neurological diseases. A provisional diagnosis of meningoencephalitis was made after review by specialist. The parents of the boy did not give consent to conduct spinal tap. Upon further examination, urgent contrast-enhanced computed tomography was done and clinical neurological assessment was not suggestive of meningoencephalitis. Antibiotics treatment for meningoencephalitis was stopped 12 h after hospitalization. Although this case was not diagnosed as aseptic meningitis, timeline of diclofenac intake, onset of symptoms, clinical manifestations and quick resolution symptoms after drug discontinuation were supportive of a temporal relationship between diclofenac and meningism. Paracetamol was given to relieve the headache, vomiting resolved after one dose of intravenous metoclopramide plus ranitidine, and patient was well throughout the 5 days in ward. This adverse effect of NSAIDs is very rare and continuous effort in pharmacovigilance can help to raise awareness among clinicians. Int J Clin Pediatr. 2020;9(1):20-23 doi: https://doi.org/10.14740/ijcp358

Clinicopathological co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis

Coexistence of distinct neurodegenerative diseases in single cases recently gathers greater attention. In this line, phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, clinicopathological co-mobidity of the two diseases has remained unproven. We investigated neuropathological characteristics of two patients who clinically presented both PSP and ALS. The patients, without family history of neurological disorders, first presented with atypical parkinsonism consistent with PSP with Richardson’s syndrome or progressive gait freezing. In a few years, they developed muscle weakness with or without pseudobulbar symptoms, which was compatible with ALS. Disease duration was 5-8 years after the onset of PSP and 1-2 years after the onset of ALS. Neuropathological findings demonstrated coexistence of PSP and ALS in both cases. Immunohistochemical examination in a recent case confirmed 4-repeat tauopathy including globose type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies, as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. In this case, immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands with 64 and 68 kDa and C-terminal fragments with 33 kDa, supporting the diagnosis of PSP and excluding other parkinsonian disorders such as corticobasal degeneration. Our cases highlight clinicopathological comorbidity of PSP and ALS in sporadic cases. The possibility of multiple proteinopathies should be considered when distinct symptoms developed in the disease course.

Enhancement of cranial nerves, conus medullaris, and nerve roots in POLG mitochondrial disease.

A 20-year-old female patient was admitted to our department due to ptosis, double vision, and difficulty walking. The symptoms had evolved during the course of 2 months. She had never been very athletic and was described as always having been a “slow runner,” but otherwise her previous history was unremarkable. There was no family history of neurologic disease. There were no preceding triggering factors such as infections, fever, or physical stress, and the patient did not take valproate. On examination, she had bilateral external ophthalmoplegia and ptosis, grade 4 proximal and distal paresis in the lower extremities, grade 4 distal paresis in the upper extremities, distal sensory loss (for all sensory modalities), and sensory ataxia. After several months, she started experiencing a very slow improvement, which is—at the present moment—still incomplete.

A Novel Pathogenic Variant in MT-CO2 Causes an Isolated Mitochondrial Complex IV Deficiency and Late-Onset Cerebellar Ataxia.

Both nuclear and mitochondrial DNA defects can cause isolated cytochrome c oxidase (COX; complex IV) deficiency, leading to the development of the mitochondrial disease. We report a 52-year-old female patient who presented with a late-onset, progressive cerebellar ataxia, tremor and axonal neuropathy. No family history of neurological disorder was reported. Although her muscle biopsy demonstrated a significant COX deficiency, there was no clinical and electromyographical evidence of myopathy. Electrophysiological studies identified low frequency sinusoidal postural tremor at 3 Hz, corroborating the clinical finding of cerebellar dysfunction. Complete sequencing of the mitochondrial DNA genome in muscle identified a novel MT-CO2 variant, m.8163A>G predicting p.(Tyr193Cys). We present several lines of evidence, in proving the pathogenicity of this heteroplasmic mitochondrial DNA variant, as the cause of her clinical presentation. Our findings serve as an important reminder that full mitochondrial DNA analysis should be included in the diagnostic pipeline for investigating individuals with spinocerebellar ataxia.

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia.

Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observedan increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.

Neurological symptoms in Hypophosphatasia.

Hypophosphatasia (HPP) is an inborn error of metabolism due to deficiency of tissue non-specific alkaline phosphatase (TNSALP). It is traditionally characterized by rickets in children and osteomalacia in adults, along with fractures, tooth loss, and muscle pain. Neurological symptoms and mental health diagnoses have not been widely reported, and we therefore report their prevalence in a cohort of patients with HPP. A retrospective chart review was performed on a series of 82 HPP patients. Patient charts were reviewed to identify the possible presence and onset of 13 common neurological symptoms. Median age was 36years (2 to 79). Seventeen had adult onset HPP (> 18years) and 65 had pediatric onset HPP (< 18years). Median time from symptom onset to HPP diagnosis was 8years (0 to 67). Seventy-four percent had a family history of bone disease, while 17% had a family history of neurologic disease. Bone problems occurred in 89%, dental problems in 77%, and muscle problems in 66%. Fatigue occurred in 66%, headache in 61%, sleep disturbance in 51%, gait change in 44%, vertigo in 43%, depression in 39%, anxiety in 35%, neuropathy in 35%, and hearing loss in 33%. The extra-skeletal manifestations of HPP, specifically neurological symptoms, have not been previously well documented. However, mental health diagnoses and neurological symptoms such as headache and sleep disturbance occur commonly in patients with HPP. The recognition of non-traditional symptoms in HPP may improve patient satisfaction, preempt costly evaluation and misdiagnosis, and may lead to further treatment options.

“Face of the giant panda” and hydrocephalus

•The face of the giant panda is a MRI sign in Wilson’s disease.•Non-pathological age-related iron accumulations is frequently seen in the red nuclei and the substantia nigra.•Due to a flow void in the aqueduct in NPH patients, the MRI looks very similar to the face of the giant panda. A 67-year-old man presented with a 6-months-history of marked gait disturbance referred to as magnetic gait. There were no other complaints. His medical history was insignificant, and he had no family history of neurological disorders. Routine bloodwork and CSF were unremarkable. The CSF opening pressure was 17 cm H2O. MRI scan of the brain showed a communicating hydrocephalus, but also “the face of the giant panda” (Fig. 1). The most likely diagnosis is:(A)Parkinson’s disease(B)Wilson’s disease(C)Normal pressure hydrocephalus(D)Progressive supranuclear palsy After tapping 30 cc cerebrospinal fluid, the gait disturbance improved remarkably for a short period of time. The diagnosis of normal pressure hydrocephalus (NPH) was made. After placement of a lumbar peritoneal shunt the gait improvement became permanent. The face of the giant panda has generally been described in Wilson’s disease [[1]Gupta A. Chakravarthi S. Goyal M.K. ‘Face of giant panda’: a rare imaging sign in Wilson's disease.QJM. 2014; 107: 579Crossref PubMed Scopus (7) Google Scholar]. However, the clinical presentation of our patient was not suspicious for this disease, and copper and ceruloplasmin values were normal. The face of the giant panda in Wilson’s disease is caused by T2 hyperintensity in the midbrain tegmentum with relative sparing of the red nuclei (eyes), the pars reticulata of the substantia nigra (ears) and the superior colliculus (mouth). In this case the “eyes” and “ears” of the panda are non-pathological age-related iron accumulations in the red nuclei and the pars reticulate of the substantia nigra respectively [[2]Aquino D. Bizzi A. Grisoli M. Garavaglia B. Bruzzone M.G. Nardocci N. et al.Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects.Radiology. 2009; 252: 165-172Crossref PubMed Scopus (215) Google Scholar]. The “mouth” of the panda is actually a flow void in the aqueduct caused by higher than normal flow velocity of cerebrospinal fluid. This flow void is frequently present in patients with NPH [[3]Krauss J.K. Regel J.P. Vach W. Jüngling F.D. Droste D.W. Wakhloo A.K. Flow void of cerebrospinal fluid in idiopathic normal pressure hydrocephalus of the elderly: can it predict outcome after shunting?.Neurosurgery. 1997; 40: 67-73PubMed Google Scholar]. The combination of non-pathological age-related iron accumulations and a flow void creates an image almost similar to the face of the giant panda, however in our case it is more a pseudo face of the giant panda, because there is no association with Wilson’s disease. The following are the Supplementary data to this article: Download .xml (.0 MB) Help with xml files Supplementary data 1