Progressive Neurological Deterioration Research Articles

Tetrahydrobiopterin deficiencies: Lesson from clinical experience.

ObjectivesThe present study describes clinical, biochemical, molecular genetic data, current treatment strategies and follow‐up in nine patients with tetrahydrobiopterin (BH4) deficiency due to various inherited genetic defects.MethodsWe analyzed clinical, biochemical, and molecular data of nine patients with suspected BH4 deficiency. All patients were diagnosed at Ege University Faculty of Medicine in Izmir, Turkey and comprised data collected from 2006 to 2019. The diagnostic laboratory examinations included blood phenylalanine and urinary or plasma pterins, dihydropteridine reductase (DHPR) enzyme activity measurement in dried blood spots, folic acid and monoamine neurotransmitter metabolites in cerebrospinal fluid, as well as DNA sequencing.ResultsAmong the nine patients, we identified one with autosomal recessive GTP cyclohydrolase I (ar GTPCH) deficiency, two with 6‐pyruvoyl‐tetrahydropterin synthase (PTPS) deficiency, three with sepiapterin reductase (SR) deficiency, and three with DHPR deficiency. Similar to previous observations, the most common clinical symptoms are developmental delay, intellectual disability, and movement disorders. All patients received treatment with l‐dopa and 5‐hydroxytryptophan, while only the ar GTPCH, the PTPS, and one DHPR deficient patients were supplemented in addition with BH4. The recommended dose range varies among patients and depends on the type of disease. The consequences of BH4 deficiencies are quite variable; however, early diagnosis and treatment will improve outcomes.ConclusionsAs BH4 deficiencies are rare group of treatable neurometabolic disorders, it is essential to diagnose the underlying (genetic) defect in newborns with hyperphenylalaninemia. Irreversible brain damage and progressive neurological deterioration may occur in untreated or late diagnosed patients. Prognosis could be satisfying in the cases with early diagnose and treatment.

Risk factors for rapid progressive neurological deterioration in patients with cervical spondylotic myelopathy

BackgroundThe rapid progressive cervical spondylotic myelopathy (rp-CSM) which had a course of CSM less than 1 month and suffered rapidly progressive neurological deterioration had few reports. Therefore, it is important for us to recognize the pathophysiology of CSM especially the rp-CSM. The study aimed to investigate the risk factors for rapidly progressive (rp) neurological deterioration in patients with cervical spondylotic myelopathy (CSM).MethodsA total of 159 patients were reviewed and divided into an rp-CSM group and a chronic-CSM (c-CSM) group. Various clinical indexes, including age, sex, Japanese Orthopaedic Association (JOA) score, intramedullary MR T2-hyperintensity, congenital/degenerative spinal stenosis, and local type of ossification of the posterior longitudinal ligament (OPLL), were analyzed, and independent risk factors were investigated.ResultsThirty-four of 159 patients (21.4%) were diagnosed with rp-CSM. All patients were followed up for a mean of 68.56 ± 14.00 months in the rp-CSM group and 62.66 ± 19.95 months in the c-CSM group. No significant difference was found in sex, mean age, smoking and drinking status, diabetes mellitus (DM), hypertension, surgery time, blood loss, JOA score, degenerative spinal stenosis, or OPLL (local). Univariate analyses demonstrated that rp-CSM patients tended to have MR T2-hyperintensity, longer hospital stay, shorter waiting time for surgery, more congenital spinal stenosis, and worse neurological function and to prefer more posterior surgeries than c-CSM patients. A multiple logistic regression analysis showed that congenital spinal stenosis and MR T2-hyperintensity were independently related to the presence of rp-CSM.ConclusionsMR T2-hyperintensity and congenital spinal stenosis were risk factors for rp-CSM. Although neurological function deteriorates rapidly, early surgical decompression is recommended and can achieve good neurological recovery after surgery, indicating that rp-CSM could be a reversible condition.

Surgical management of complex post-tuberculous kyphosis among African patients: clinical and radiographic outcomes for a consecutive series treated at a single institution in West Africa.

Retrospective review of consecutive series. To assess the clinical and radiographic outcomes after surgical management of post-tuberculous kyphosis. Post-tuberculous (TB) kyphosis can lead to progressive pulmonary and neurological deterioration. Surgery is indicated to decompress neural elements and correct the spine deformity. Although posterior vertebral column resection (PVCR) has been established as the treatment of choice for severe TB kyphosis, there is paucity of studies on the clinical outcomes among patients treated in West Africa. Clinical and radiographic data of 57 patients (pts) who underwent surgical correction of post-TB kyphosis at a single site in West Africa between 2013 and 2018 (≥ 2-year follow-up in 36 pts, ≥ 1-year FU in 21 pts). Pre- and post-op SRS scores and radiographic outcomes were compared using Paired t test. 57 patients, 36M:21F. Mean age 19 (11-57years). 22/57 pts (39.3%) underwent pre-op halo gravity traction (HGT) for an average duration of 86days (8-144days). HGT pts had a higher baseline regional kyphosis (125.1 ± 20.9) compared to non-HGT pts (64.6 ± 31.8, p < 0.001). Post-HGT regional kyphosis corrected to 101.2 ± 23 (24° correction). 53 pts (92.9%) underwent posterior-only surgery and 4 (7.0%) combined anterior-posterior surgery. 39 (68.4%) had PVCR, 11 (19.3%) PSO, and 16 (28.1%) thoracoplasty. Intraoperative neuromonitoring (IOM) signal changes occurred in 23/57 pts (≈ 40%), dural tear in 5 pts (8.8%), pleural tear in 3 pts (5.3%), ureteric injury in 1 pt (1.7%), and vascular injury in 1 pt (1.7%). Post-op complications included four (7.0%) infection, three (5.3%) implant related, two (3.5%) radiographic (one PJK and one DJK), one (1.7%) neurologic, one (1.7%) wound problem, and two (3.5%) sacral ulcers. IOM changes were similar in the VCR (48.7%) and non-VCR (23.5%) pts, p > 0.05. Complication rates were similar among HGT and non-HGT groups. Significant improvements from baseline were seen in the average SRS Total and domains scores and radiographic measurements for patients who attained 2-year follow-up. PVCR ± HGT can provide safe and optimal correction in cases of severe post-TB kyphosis with good clinical and radiographic outcomes in underserved regions.

A Novel Mutation (p.Met1?) of a Cuban Patient in the NAGLU Gene with Mucopolysaccharidosis IIIB

Abstract Mucopolysaccharidosis III (MPSIII) or Sanfilippo syndrome is an autosomal recessive disorder of lysosomal metabolism. MPS III is caused by mutations in genes that encode for the enzymes involved in the degradation of heparan sulfate. It is classified into 4 subtypes (MPSIII A-D). MPS IIIB is induced by mutations in the gene encoding the alpha-N-acetylglucosaminidase enzyme. We report a 6-year-old boy with phenotypic findings of Sanfilippo syndrome type B, such as mild coarse facie, clear corneas, hirsutism, hepatomegaly, mild joint stiffness and mild dysostosis multiplex. He also presents frequent upper respiratory infections, bilateral hearing loss, sleep disturbances, progressive neurologic deterioration and behavioral problems. He is compound heterozygous for the NAGLU gene (c.503G˃A; p.Trp168Ter/ c.3G˃A; p.met1?). One of the mutation was described in two patients before. A novel pathogenic variant was detected.

Severe isolated sulfide oxidase deficiency with a novel mutation

Isolated sulfite oxidase deficiency (ISOD), caused by mutations in SUOX gene, is an autosomal recessive disease manifesting with early onset seizures, developmental delay, microcephaly, and spasticity. It mimics hypoxic-ischemic encephalopathy (HIE) in the neonatal period and is characterized by progressive severe neurological impairment due to accumulation of toxic metabolites. This report presents a late diagnosed male patient with ISOD manifesting with neonatal-onset seizures, developmental delay, microcephaly, and spastic quadriplegia. Brain magnetic resonance imaging of the patient showed bilateral subcortical multi-cystic encephalomalacia involving bilateral parieto-occipital regions. A novel homozygous c.590_595delAGCCTC in-frame deletion in SUOX gene was identified in the patient, while both parents were heterozygous for that mutation. The mutation identified in our patient causes severe ISOD. Early diagnosis of ISOD is essential for accurate genetic counseling and achieving prenatal diagnosis. Screening for urinary sulfite in patients with neonatal or early infantile onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking HIE helps in early diagnosis.

Relationship between Machine-Learning Image Classification of T2-Weighted Intramedullary Hypointensity on 3 Tesla Magnetic Resonance Imaging and Clinical Outcome in Dogs with Severe Spinal Cord Injury.

Early prognostic information in cases of severe spinal cord injury can aid treatment planning and stratification for clinical trials. Analysis of intraparenchymal signal change on magnetic resonance imaging has been suggested to inform outcome prediction in traumatic spinal cord injury. We hypothesized that intraparenchymal T2-weighted hypointensity would be associated with a lower potential for functional recovery and a higher risk of progressive neurological deterioration in dogs with acute, severe, naturally occurring spinal cord injury. Our objectives were to: 1) demonstrate capacity for machine-learning criteria to identify clinically relevant regions of hypointensity and 2) compare clinical outcomes for cases with and without such regions. A total of 95 dogs with complete spinal cord injury were evaluated. An image classification system, based on Speeded-Up Robust Features (SURF), was trained to recognize individual axial T2-weighted slices that contained hypointensity. The presence of such slices in a given transverse series was correlated with a lower chance of functional recovery (odds ratio [OR], 0.08; confidence interval [CI], 0.02-0.38; p < 10-3) and with a higher risk of neurological deterioration (OR, 0.14; 95% CI, 0.05-0.42; p < 10-3). Identification of intraparenchymal T2-weighted hypointensity in severe, naturally occurring spinal cord injury may be assisted by an image classification tool and is correlated with functional recovery.

The juvenile gangliosidoses: A timeline of clinical change

BackgroundThe gangliosidoses are rare inherited diseases that result in pathologic accumulation of gangliosides in the central nervous system and other tissues, leading to severe and progressive neurological impairment and early death in the childhood forms. No treatments are currently approved for the gangliosidoses, and development of treatments is impaired by limited understanding of the natural history of these diseases. ObjectiveThe objective of this study is to improve understanding of the juvenile gangliosidoses phenotypes and the late-infantile phenotypic subtype. MethodsThrough a prospective natural history study of subjects with juvenile GM1- and GM2-gangliosidosis, a timeline of clinical changes was developed for the classic juvenile phenotypes and the late-infantile phenotypes and results of serial neurodevelopmental testing was analyzed. ResultsSeveral candidate ‘outcome measures’ were identified: changes in ambulation and verbalization skills, the communication domain from neurodevelopmental testing and the caregiver-reported socialization domain. ConclusionsThe most common symptoms leading caregivers to seek a genetic diagnosis were changes in ambulation and verbalization.

QOLP-11. QUALITY OF END-OF-LIFE CARE IN PATIENTS WITH HIGH GRADE GLIOMAS

Abstract BACKGROUND Patients with high-grade gliomas (HGG) face unique challenges toward the end of life (EoL), given their aggressive disease trajectory and progressive neurologic deterioration. The discipline of supportive care (SC) has been beneficial in improving quality of EoL care in patients with non-CNS cancers, however data on its contribution to EoL care in patients with HGG is lacking. METHODS We retrospectively reviewed charts of MDA patients from 2010-2017 to compare the demographic factors and clinical and quantitative EoL outcomes between patients with HGG--who were either referred (n=54) or not referred (n=85) to SC--and patients with non-CNS cancers who were referred to SC (n=72). A composite score for poor EoL quality outcomes was used with the following variables: death in hospital, chemotherapy within 14d of death, ≥2 hospitalizations, ≥2 ER visits, ICU admission and &amp;gt;14 days hospitalization within the last 30 days of life. Patients were eligible for SC based on poor/declining performance status, &amp;lt; 6 month prognosis, or recurrent GBM. RESULTS Patients with HGG had similar EoL quality regardless of SC referral, and these patients in general had better EoL quality than patients with non-CNS cancers (p=0.005). EoL quality was significantly worse in HGG patients who received late versus early SC referrals (p=0.0066). Both weakness (OR=1.27, p=0.0289) and number of disease progressions (OR=2.618, p=0.001) at the time of eligibility for SC were predictive of poorer quality of EOL. The majority of HGG patients (61.2%) eligible for SC were not referred. CONCLUSIONS EoL outcomes in patients with malignant gliomas are overall better than those of patients with non-CNS cancer, however certain clinical features and later SC referral remain significantly associated with poorer EoL quality. Our data suggest that the role of SC in improving EoL outcomes in our patient population warrants further evaluation.

NCOG-03. FACTORS ASSOCIATED WITH ADJACENT LEVEL TUMOR PROGRESSION IN PATIENTS RECEIVING SEPARATION SURGERY FOLLOWED BY SPINE STEREOTACTIC RADIOSURGERY FOR METASTATIC EPIDURAL SPINAL CORD COMPRESSION

Abstract INTRODUCTION Separation surgery followed by spine stereotactic radiosurgery (SSRS) has been shown to achieve favorable rates of local tumor control and patient-reported outcomes in patients with metastatic epidural spinal cord compression (MESCC). If left untreated, MESCC causes severe pain, progressive neurological impairment, and eventual paraplegia with a median survival of 3-6 months. The present study aimed to identify factors associated with adjacent level progression and examine its impact on overall survival (OS) in this population. METHODS This study included 39 patients who received separation surgery followed by SSRS for MESCC. Preoperative, postoperative, and post-SSRS MRIs were used to measure amount of epidural disease, amount of local bone marrow involvement, and adjacent level epidural (AEP) and osseous (AOP) progression. Factors associated with AEP and AOP were examined using the log-rank test and cox proportional hazards modeling. RESULTS Median OS in our cohort was 14.7 mo (2.07-96.3). AEP and AOP were observed in 4/39 (10.3%) and 16/39 (41.0%) patients at a mean of 6.1±5.4 mo and 5.3±5.3 mo post-SSRS, respectively. AEP (7.52 vs. 17.1 mo, p = 0.014) and AOP (13.0 vs. 17.1 mo, p = 0.047) were each significantly associated with decreased OS. Factors associated with AEP included primary tumor histology, low-dose hypofractionated SSRS, increased time from surgery to SSRS, and greater amount of local epidural disease preoperatively (p &amp;lt; 0.05). Factors associated with AOP included greater amount of local bone marrow infiltration by tumor pre- and postoperatively and greater amount of local epidural disease postoperatively (p &amp;lt; 0.05). Primary tumor histology and increased time from surgery to SSRS were associated with AOP by trend (p &amp;lt; 0.10). CONCLUSION This study identifies factors associated with adjacent level progression and shows that AEP and AOP are associated with shorter OS in patients receiving separation surgery followed by SSRS for MESCC.

Metreleptin for the treatment of progressive encephalopathy with/without lipodystrophy (PELD) in a child with progressive myoclonic epilepsy: a case report

BackgroundA number of genetic syndromes associated with variants in the BSCL2/seipin gene have been identified. Variants that cause skipping of exon 7 are associated with progressive encephalopathy with/without lipodystrophy (PELD), which is characterized by the development of progressive myoclonic epilepsy at a young age, severe progressive neurological impairment, and early death, often in childhood. Because the genetic basis of PELD is similar to that of congenital lipodystrophy type 2, we hypothesized that a patient with PELD may respond to treatments approved for other congenital lipodystrophic syndromes.Case presentationWe describe a 5-year-old boy with an extremely rare phenotype involving severe progressive myoclonic epilepsy who received metreleptin (a recombinant analogue of leptin) to control metabolic abnormalities. At the age of two, he had no subcutaneous adipose tissue, with hypertriglyceridemia, hypertransaminasemia and hepatic steatosis. He also had a moderate psychomotor delay and generalized tonic seizures. At 4 years, he had insulin resistance, hypercholesterolemia, hypertriglyceridemia, mild hepatosplenomegaly and mild hepatic steatosis; he began a hypolipidemic diet. Severe psychomotor delay and myoclonic/myoclonic atonic seizures with absences was evident. At 5 years of age, metreleptin 0.06 mg/kg/day was initiated; after 2 months, the patient’s lipid profile improved and insulin resistance resolved. After 1 year of treatment, hepatic steatosis improved and abdominal ultrasound showed only mild hepatomegaly. Seizure frequency decreased but was not eliminated during metreleptin therapy.ConclusionsMetreleptin may be used to control metabolic disturbances and may lead to better seizure control in children with PELD.

Rasmussen’s encephalitis and central precocious puberty. Neuroendocrinological characterization of three cases

PurposeRasmussen’s encephalitis (RE) is a chronic neurological disorder characterized by inflammation of the cerebral cortex, mainly unilateral, that leads to drug-resistant epilepsy and progressive neurological impairment. Central Precocious Puberty (CPP) is uncommon, albeit increased in frequency in patients with neurological conditions and the physiopathological bases of these associations remains unclear in most cases. Epilepsy has been proposed to play a role, as well as the accumulation of substances produced as a result of metabolism or tissue degeneration in some neurodegenerative diseases. However, CPP has not been previously described in patients with RE. MethodsFrom a series of patients affected by RE followed-up at a referral center, an in-depth review of the characteristics of those who developed CCP was carried out. ResultsThree cases were identified, representing a relative frequency of 21.4 % for CPP. They were girls, of Caucasian ethnicity, without family history of CPP or any image-identified abnormalities in the hypothalamic area. In two cases CPP manifested immediately before the onset of the epilepsy (prior to the diagnosis of RE) and in the other, after epilepsy onset but coinciding with a worsening of the seizures. A GnRH test with pubertal response confirmed CPP in the three cases. ConclusionThe high proportion of CPP in patients affected by RE suggested a plausible relationship between these two entities. Various factors involved, including neuroinflammation, are hypothesized in the present study. However, further studies are needed to elucidate the pathophysiological bases, which could provide insight in the understanding of both entities.

Differential diagnosis of progressive intellectual and neurological deterioration in children.

AimTo report the differential diagnosis in children with progressive intellectual and neurological deterioration (PIND) in the UK.MethodSince 1997 the PIND Study has searched for variant Creutzfeldt‐Jakob disease (vCJD) in children, using the British Paediatric Surveillance Unit to perform prospective surveillance of those younger than 16 years with PIND.ResultsFrom May 1997 to October 2019, 2255 children meeting PIND criteria had been notified, of whom 2008 (1085 males, 923 females) had underlying diagnoses. There were over 220 different diseases, including six cases of vCJD. The numbers presenting in four age groups were: <1 year, 805 (40%); 1 to 4 years inclusive, 825 (41%); 5 to 9 years inclusive, 264 (13%); and 10 to 15 years inclusive, 114 (6%). The two largest ethnic groups were White and Pakistani (58.2% and 17% of diagnosed cases). The most common diseases in these two ethnic groups are shown for the four age groups. The distribution of diseases varied with age but was quite similar in White and Pakistani children.InterpretationThis paper provides a unique guide to the complex differential diagnosis of childhood PIND, showing considerable differences between four age groups, but similarities between ethnic groups. The PIND Study still provides the only systematic surveillance for vCJD in children in the UK.What this paper adds The prevalence of diseases causing childhood progressive intellectual and neurological deterioration in the UK is low (approximately 0.1/1000 live births).There were more than 220 different disorders, mainly genetically determined.The majority of disorders presented early in childhood: 81% before the age of 5 years.There were similarities in the disease spectrum in White and Pakistani children.

Hydrocephalus in children – A rare case of pineal cavernoma and literature review

Background: Cavernous malformations prevalence ranges from 0.4 to 0.6% and accounts for 5–15% of all central nervous system vascular malformations. Pineal cavernomas constitute <1% of all locations published in the literature, with a total of 26 cases reported, only 5 regarding the pediatric population until 2020. Overall annual hemorrhage rate is 2.4%. Symptoms are often due to hydrocephalus and intracranial hypertension.Case Description: We report a case of a 5-year-old child with visual disturbances, headache, and progressive neurologic deterioration. MR showed a lesion in the pineal region and triventricular hydrocephalus. She was submitted to endoscopic third ventriculostomy and total excision of the lesion by the infratentorial supracerebellar approach a few days later. Histopathological examination confirmed a pineal cavernous malformation. The patient returned to her normal life without any neurologic deficit and a normal development.Conclusion: The ideal treatment is primary lesion removal; however, due to the infrequency and because it is a curable lesion, studies seeking to deepen the knowledge of this disease are considered relevant.

Meningeal Relapse of Nodular Lymphocyte Predominant Hodgkin Lymphoma Transformed to T-Cell/Histiocyte-Rich Large B-Cell Lymphoma: A Case Report

Central nervous system involvement in Hodgkin lymphoma is extremely rare, especially in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which usually carries a favorable prognosis. Here we report a case of a young patient with NLPHL, who developed a progressive and fatal neurological deterioration requiring a very extensive work-up including two biopsies to obtain the diagnosis of T-cell/histiocyte-rich large B-cell lymphoma like transformation. This report, which includes post-mortem analysis, highlights the correlations between clinical, radiological, and biological data but also the difficulties encountered in reaching the correct diagnosis.

The Wiedemann-Rautenstrauch or Neonatal Progeroid Syndrome: Report of a Patient with Gingival Hyperplasia and Severe Anterior Open Bite

Introduction: The Wiedemann-Rautenstrauch syndrome (WRS) is a rare progeroid syndrome with an autosomal recessive pattern of inheritance. The main clinical features include severe intrauterine and postnatal growth failure, distinctive facial appearance, hydrocephaly, prominent scalp veins, absence of subcutaneous fat, sparse hair of the scalp, eyebrows, and eyelashes, generalized lipoatrophy, psychomotor delay, progressive neurological deterioration, and short life expectancy. Natal teeth and micrognathia are reported as the oral manifestations of this syndrome. Case Presentation: Here is the report of a 6.5-year-old female patient with clinical signs of WRS referred to the Department of Periodontology of Shiraz School of Dentistry with the chief complaint of toothache and gingival hyperplasia. Carious teeth were extracted, and excess gingival tissue was removed through a surgical procedure under general anesthesia. The patient was the first case with a concomitant severe anterior open bite. Conclusions: Therapies for WRS are symptomatic, requiring the coordinated efforts of a team of specialists. Dentists and oral surgeons can be recruited by pediatricians and family physicians to improve the quality of life of such patients.

ABCL-311: The Burden of Non-Hodgkin Lymphoma Developed in an Ataxia Telangiectasia Child

Context: Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive neurologic impairment, cerebellar ataxia, immunodeficiency, ocular and cutaneous telangiectasia, and predisposition to malignancy. AT patients have a 100-fold increased risk for the development of lymphoid malignancies, particularly non-Hodgkin lymphomas (NHL). In these patients, severe pulmonary infections are the most frequent cause of death, followed by the combination of pulmonary infection and malignancy. Objective: Evaluation of a clinical case of hematologic malignancy in a child diagnosed with primary immunodeficiency (PID) AT. Methods: We analyzed clinical records, biopsy of lymph node, evaluation of serum immunoglobulins by ELISA, and neurologic involvement by MRI. Results: A 13-year-old boy diagnosed as AT was referred to the Oncologic hospital due to multiple lymphadenopathy. He was born to non-consanguineous healthy parents. Previous medical history revealed waddling gait when he started walking. He was consulted by a neuropediatrician as being suspected of cerebral palsy. Brain MRI revealed cerebellar vermis hypoplasia with enlargement of cisterna magna. The patient also experienced recurrent respiratory infections. At the age of 12 years, the patient had fever of unknown origin for several months, which was unresponsive to antibiotics, and the patient's cervical and submandibular lymph nodes began to enlarge, which progressed. A biopsy was performed, and the patient was diagnosed with NHL, DLBCL type. On presentation, the patient had multiple enlarged cervical, submandibular, axillary, and inguinal lymph nodes and telangiectasia of the bulbar conjunctiva. Neurologic examination revealed decreased tendon reflexes, ataxia, and dysarthria. Laboratory investigations identified a normal complete blood count and biochemistry tests, but the alpha-fetoprotein level was high. There were decreased levels of IgA and IgG and a high level of IgM. Computed tomography showed involvement of cervical, submandibular, axillary, upper mediastinum, and hilum lymph nodes. The patient received CHOP chemotherapy with a reduced dose. The treatment was well-tolerated, despite neutropenia, grade 3 mucositis, and neutropenic fever. Unfortunately, at the last interruption after chemotherapy, the patient had chickenpox and died due to multiple organ failure. Conclusions: Patients with PID have a high risk of developing cancer. It is important to consider AT in a child with pre-existing ataxia or hematologic malignancy that was diagnosed at a younger age than expected.

Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome

Leigh syndrome is a genetically heterogeneous disorder resulting from deficient oxidative energy biogenesis. The syndrome is characterized by subacute episodic decompensations, transiently elevated lactate, and necrotizing brain lesions most often in the striatum and brainstem. Acute decompensation is often triggered by viral infections. Sequalae from repeated episodes leads to progressive neurological deterioration and death. The severity of Leigh syndrome varies widely, from a rapid demise in childhood to rare adult presentations. Although the causes of Leigh syndrome include genes affecting a variety of different pathways, more than 75 of them are nuclear or mitochondrial encoded genes involved in the assembly and catalytic activity of mitochondrial respiratory complex I.Here we report the detailed clinical and molecular phenotype of two adults with mild presentations of NDUFS3 and NDUFAF6-related Leigh Syndrome. Mitochondrial assays revealed slightly reduced complex I activity in one proband and normal complex I activity in the other. The proband with NDUFS3-related Leigh syndrome was mildly affected and lived into adulthood with novel biallelic variants causing aberrant mRNA splicing (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C). The proband with NDUFAF6-related Leigh syndrome had biallelic variants that cause defects in mRNA splicing (NM_152416.3:c.371 T > C; p.Ile124Thr; NM_152416.3:c.420 + 2_420 + 3insTA). The mild phenotypes of these two individuals may be attributed to some residual production of normal NDUFS3 and NDUFAF6 proteins by NDUFS3 and NDUFAF6 mRNA isoforms alongside mutant transcripts. Taken together, these cases reported herein suggest that splice-regulatory variants to complex I proteins could result in milder phenotypes.

Generation of an iPSC line (IMAGINi022-A) from a patient carrying a SOX10 missense mutation and presenting with deafness, depigmentation and progressive neurological impairment.

Mutations of SOX10 result in a broad range of phenotypes including Waardenburg syndrome (WS types 2 and 4) that can be found in association with peripheral demyelinating neuropathy and/or central dysmyelinating leukodystrophy. Here, we generated induced pluripotent stem cells (iPSCs) from a patient carrying a de novo heterozygous missense mutation in the SOX10 gene (MIM* 602229, NM006941.3c.523C>G; p.Pro175Ala) presenting with deafness, depigmentation and progressive neurological impairment. Cells were reprogrammed by non-integrative viral transduction from blood sample, have normal karyotype, express pluripotency markers and are able to differentiate into the three germ cell layers.

The Influence of Depression and Anxiety on Neurological Disability in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), affecting mostly young-aged people. As a chronic incurable disease, in most cases, it can lead to progressive neurological impairment and severe disability. Depression and anxiety are major distress factors for MS patients, being considerably aggravating elements for their functional capacity. In this study, we analysed the mood disorder distribution and the possible correlations between depression, anxiety, automatic negative thoughts, and MS disability. We took into consideration 146 MS patients, who completed a series of questionnaires: Beck Depression Inventory II (BDI-II), Endler Multidimensional Anxiety Scales-State (EMAS-S), and Automatic Thoughts Questionnaire (ATQ). The Expanded Disability Status Scale (EDSS) was used to measure the neurological disability. Of all patients, 30.1% had symptoms for depression and 11% presented suicidal thoughts. After analysing the correlation index between each variable, we found that there is a mild positive correlation between depression and the EDSS score and between anxiety and the EDSS score. A difference is found in the test scores according to the type of the MS disease. Also, automatic negative thoughts are strongly correlated with depression and anxiety, but do not mediate the path between psychological comorbidities and neurological impairment. Sociodemographic features and interferon-beta treatment were not related to the intensity of the mood disorders. The study suggests that depression and anxiety are frequently encountered among MS patients and these mental disfunctions have an impact on their disability. A proper identification of these risk factors may improve the quality of life for these patients.

New treatment modalities in NF-related neuroglial tumors.

The management of low-grade gliomas (LGGs) and other neuroglial tumors in children with neurofibromatosis type 1 (NF1) has not changed over the past 2-3 decades. With the widespread utilization of chemotherapy for younger children with progressive LGGs, outcomes have been good for most patients who have required treatment. However, some may progress after the initiation of chemotherapy and others, although radiographically responding or with stable disease, may develop progressive neurologic and visual deterioration. Molecular-targeted therapy has become an option for patients who have progressed after receiving chemotherapy and the mTOR inhibitors and bevacizumab have already shown some degree of efficacy. However, the greatest impact has been the introduction of the MEK inhibitors. A variety of different MEK inhibitors are in clinical trials and have already demonstrated the ability to result in radiographic tumor shrinkage in the majority of children with NF1 and progressive LGGs. Because of this efficacy, the MEK inhibitors have moved rapidly from phase I studies to ongoing phase III studies comparing their benefit directly to that of chemotherapy. The long-term ability of these agents to not only control disease, but improve visual and/or neurological function, as well as their short- and long-term safety, are open questions that can only be answered by well-constructed prospective, often randomized, clinical trials.