Estimation of Ambulation and Survival in Neurodegeneration with Brain Iron Accumulation Disorders.

BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course. OBJECTIVES: To estimate the probability of preserving ambulatory ability and survival in NBIA. METHODS: In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods. RESULTS: One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03). CONCLUSIONS: KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death.

Identical twins with progressive kyphoscoliosis and ophthalmoplegia.

The possible differential diagnoses for children presenting with kyphoscoliosis, skeletal deformities and ophthalmoplegia are diverse. We present 11-year-old identical twins with these symptoms, with interesting etiological concern for those practicing in the fields of neurology, pediatrics, spine surgery and related specialties. A new presentation for a rare genetic condition was the final diagnosis for our patients. In this movement disorder round we describe our approach to this clinical constellation and discuss clinical significance of this genetic condition.

Long term follow-up results of deep brain stimulation of the Globus pallidus interna in pediatric patients with DYT1-positive dystonia.

OBJECTIVES: Primary generalized dystonia (PGD) due to heterozygous torsin 1A (TOR1A) gene mutation (DYT1) is a childhood onset dystonia with rapid deterioration of symptoms, leading to severe disability in adolescence. Globus pallidus interna deep brain stimulation (GPi-DBS) has been shown to provide significant improvement in these cases. METHODS: This was a retrospective study of TOR1A mutation positive dystonia patients, conducted at a university hospital from 2006 to 2018. Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS) was used to evaluate dystonia severity before and after surgery. Emergence of postsurgical parkinsonian symptoms was evaluated using the Unified Parkinson Disease Rating Scale (UPDRS) part III. Montreal Cognitive Assessment (MOCA) was applied to assess cognitive dysfunction. SPSS version 18 was used for data analysis. RESULTS: Eleven patients entered for analysis with an average age of 22.36 (±3.35) years (range: 18-28). Seven patients (63.6 %) were female. Mean follow-up period was 8.72 (±0.87). Difference between baseline and most recent BFM scores was significant (disability: 10.5 ±4.52 versus 2.09 (±3.20), P: 0.001; severity: 48.45 (±17.88) versus 9.36 (±10.47), P<0.001). The mean MOCA and UPDRS III scores after 7-9 years of DBS were 27.18 (±2.99), and 6.09 (±4.15), respectively. CONCLUSION: Our experience confirms that GPi-DBS in pediatric patients with DYT1 dystonia is overall successful, with significant and long-lasting positive effects on motor and cognitive functions. There was no prominent side effect in long-term follow up.

Parkinsonism management issues in a patient with exhausted subthalamic deep brain stimulation battery, stricken by severe acute respiratory syndrome coronavirus 2.

Background: Nowadays, many neurological conditions, including Parkinson's disease (PD), are treated with deep brain stimulation (DBS). Life-threatening consequences can occur from DBS hardware failure or sudden implantable pulse generator (IPG) battery depletion. This issue may potentially worsen in concomitance with medical or infectious conditions, requiring stronger emergency management. Methods: We present here a 58 year-old PD patient with DBS, whose IPG replacement surgery was complicated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and we report management of this patient along with recommendations for patients with similar situation. Results: As the newly-emerged coronavirus disease 2019 (COVID-19) is now announced to be pandemic, new protocols and specific measures for each individual group of patients with chronic diseases seem obligatory. Regarding our recent experience with a patient suffering from PD, on DBS treatment, who needed hospitalization, we felt useful to share our experience as a recommended protocol for similar patients in the time of current pandemic. Conclusion: Close monitoring of laboratory and clinical signs should be warranted in patients with PD awaiting IPG replacement in order to be prepared in these novel conditions that may precipitate an akinetic crisis/dystonic storm and to prevent life-threatening complications during the current pandemic.

Anteromedial GPi deep brain stimulation in Tourette syndrome: The first case series from Iran.

OBJECTIVES: Tourette syndrome (TS) is a neuropsychiatric disorder characterized by childhood onset motor and phonic tics. In refractory cases, deep brain stimulation (DBS) with different targets including anteromedial Globus pallidus (AM-GPi) looks promising. PATIENTS AND METHODS: Patients with TS diagnosed according to DSM-IV TR criteria with severe medication-recalcitrant disease referred to our DBS clinic, were recruited for this study. They underwent bilateral AM-GPi DBS with Model 3389, Medtronic electrodes. Patients were assessed using Yale Global Tic Severity Scale (YGTSS) and Gilles de la Touretts syndrome-quality of life (GTS-QOL) questionnaire before and one year after DBS. RESULTS: Six patients (four men and two women) with severe medication-recalcitrant TS, mean age of 26.33 ±â€¯7.25 years fulfilled the follow up visits. All patients revealed significant improvement in tics severity one year after surgery. Based on YGTSS, total tic severity score decreased from 75.66 ±â€¯16.54 to 28.33 ±â€¯13.95, P-value:0.005. Quality of life improved significantly after DBS (26.66 ±â€¯20.65 before and 70.00 ±â€¯17.88 one year after surgery, P-value:0.02). CONCLUSIONS: Results of our study in accordance to previous ones suggest AM-GPi DBS as an effective and well-tolerated therapeutic modality for patients with medication refractory TS.

Spatial distance between anatomically- and physiologically-identified targets in subthalamic nucleus deep brain stimulation in Parkinson's disease.

BACKGROUND: Subthalamic nucleus (STN) stimulation is the treatment of choice for carefully chosen patients with idiopathic Parkinson's disease (PD) and refractory motor fluctuations. We evaluated the value of intraoperative electrophysiology during STN deep brain stimulation (DBS) procedures in refining the anatomically-defined target. METHODS: We determined the spatial distance between the anatomical and physiological targets along x, y and z axes in 50 patients with PD who underwent bilateral subthalamic nucleus DBS surgery. RESULTS: The mean spatial distance between anatomical and functional targets was 1.84 ± 0.88 mm and the least distances in different methods were 0.66 mm [standard error (SE): 0.07], 1.07 mm (SE: 0.08) and 1.01 mm (SE: 0.08) on x, y and z axes, respectively, for the combined method. CONCLUSION: The most physiologically-accurate anatomical targeting was achieved via a combination of multiple independent methods. There was a statistically significant difference between the anatomical and functional targets in all methods (even the combined) on the y coordinate, emphasizing the need for intra-operative electrophysiological monitoring to refine the anatomico-radiologically-defined target.

Identification of p.Gln858* in ATP13A2 in two EOPD patients and presentation of their clinical features.

We present results of homozygosity mapping in two siblings affected with early onset Parkinson's disease (EOPD) and mutation screening of ATP13A2 in these and other Iranian EOPD patients. Genome-wide SNP homozygosity analysis revealed linkage to a locus that included ATP13A2, and sequencing of the gene revealed a novel p.Gln858*-causing mutation in the homozygous state in the siblings. Sequencing of the gene in seven other unrelated EOPD patients previously shown not to have mutations in PRKN, DJ-1, PINK1, and LRRK2 identified the same homozygous p. Gln858*-causing mutation in another patient. Haplotype analysis revealed that two alleles harboring the mutation were not identical by decent. The variation identified represents the 13th known disease causing mutation in ATP13A2. The clinical features of the patients who harbored the mutation are compared to those of previously reported patients with mutations in ATP13A2. Bradykinesia and rigidity, but not tremor, were reported in nearly all the patients. l-dopa administration, though initially effective, usually caused dyskinesia upon prolonged usage. Eye movement abnormalities including saccades and supranuclear gaze palsy, were almost always observed. Dystonia and bulbar anomalies were common but more variable manifestations. Although a degree of cognitive decline was found in most of the patients, the decline was often mild and absent in one patient. Age at onset of symptoms was usually in the second decade of life, and sometimes in the third decade.

PRKN, DJ-1, and PINK1 screening identifies novel splice site mutation in PRKN and two novel DJ-1 mutations.

We present results of mutation screening of PRKN gene in 93 Iranian Parkinson's disease (PD) patients with average age at onset (AAO) of 42.2 years. The gene was screened by direct sequencing and by a semi-quantitative PCR protocol for detection of sequence rearrangements. Heterozygous rearrangements were tested by reverse transcription-polymerase chain reaction (RT-PCR). Nine different PRKN mutations were found. One of these, IVS9+1G>A, affects splicing and is novel. Two mutated PRKN alleles were observed in each of 6 patients whose average AAO was 25.7 years. Only 1 patient carried a single mutated allele and his AAO was 41 years. Among patients with AAO of <30 years, 31.3% had two mutated alleles, while only 2.6% with AAO of >30 years carried a PRKN mutation. Analysis of PRKN by RT-PCR led to identification of a novel exon expressed in leukocytes of control and PD individuals. The alternatively spliced transcript if translated would code a protein without a RING Finger 2 domain. Its functional relevance remains to be shown. DJ-I and PINK1 were also screened. Two novel DJ-1 mutations, c.91-2A>G affecting splicing and c.319G>C causing Ala107Pro, were observed among patients with AAO of <31 years, suggesting that PD in a high fraction (>12%) of this group of Iranian patients may be due to mutations in DJ-1. Mutations in PINK1 were not observed. Our results complement previous findings on LRRK2 mutations among Iranian PD patients.

A clinic-based screening of mutations in exons 31, 34, 35, 41, and 48 of LRRK2 in Iranian Parkinson's disease patients.

We present results of mutation screening of exons 31, 34, 35, 41, and 48 of LRRK2 in 205 Iranian Parkinson's disease patients. Sixteen percent of the cases were familial. Although age was not a factor in patient recruitment, the Iranian cohort was relatively young (average age at onset of disease: 48.9 years). A notably high male to female ratio (2.96:1) and earlier age at onset (by 2.9 years) in men were observed. A known disease-associated variation, c.C4321T causing R1441C, and IVS31 + 3A > G, a variation that may be associated, were observed. Therefore, disregarding IVS31 + 3A > G, disease status in at least 0.5% of our young cohort and in 3.5% of the familial cases was associated with a mutation in the five exons of LRRK2 screened. Interestingly, the variation causing p.G2019S was not observed.