Identification of SYNJ1 in a Complex Case of Juvenile Parkinsonism Using a Multiomics Approach.

This study aimed to elucidate the genetic causes underlying the juvenile parkinsonism (JP) diagnosed in a girl with several family members diagnosed with spinocerebellar ataxia type 2 (SCA2). To achieve this, whole-exome sequencing, analysis of CAG repeats, RNA sequencing analysis on fibroblasts, and metabolite identification were performed. As a result, a homozygous missense mutation SNP T>C (rs2254562) in synaptojamin 1 (SYNJ1), which has been implicated in the regulation of membrane trafficking in the synaptic vesicles, was identified. Additionally, we observed overexpression of L1 cell adhesion molecule (L1CAM), Cdc37, GPX1, and GPX4 and lower expression of ceruloplasmin in the patient compared to the control. We also found changes in sphingolipid, inositol, and inositol phosphate metabolism. These findings help to clarify the mechanisms of JP and suggest that the etiology of JP in the patient may be multifactorial. This is the first report of the rs2254562 mutation in the SYNJ gene identified in a JP patient with seizures and cognitive impairment.

Neurophysiological assessment of juvenile parkinsonism due to primary monoamine neurotransmitter disorders.

No studies have investigated voluntary movement abnormalities and their neurophysiological correlates in patients with parkinsonism due to inherited primary monoamine neurotransmitter (NT) disorders. Nine NT disorders patients and 16 healthy controls (HCs) were enrolled. Objective measurements of repetitive finger tapping were obtained using a motion analysis system. Primary motor cortex (M1) excitability was assessed by recording the input/output (I/O) curve of motor-evoked potentials (MEP) and using a conditioning test paradigm for short-interval intracortical inhibition (SICI) assessment. M1 plasticity-like mechanisms were indexed according to MEPs amplitude changes after the paired associative stimulation protocol. Patient values were considered abnormal if they were greater or lower than two standard deviations from the average HCs value. Patients with aromatic amino acid decarboxylase, tyrosine hydroxylase, and 6-pyruvoyl-tetrahydropterin synthase defects showed markedly reduced velocity (5/5 patients), reduced movement amplitude, and irregular rhythm (4/5 patients). Conversely, only 1 out of 3 patients with autosomal-dominant GTPCH deficiency showed abnormal movement parameters. Interestingly, none of the patients had a progressive reduction in movement amplitude or velocity during the tapping sequence (no sequence effect). Reduced SICI was the most prominent neurophysiological abnormality in patients (5/9 patients). Finally, the I/O curve slope correlated with movement velocity and rhythm in patients. We provided an objective assessment of finger tapping abnormalities in monoamine NT disorders. We also demonstrated M1 excitability changes possibly related to alterations in motor execution. Our results may contribute to a better understanding of the pathophysiology of juvenile parkinsonism due to dopamine deficiency.

Genetic Variations and Neuropathologic Features of Patients with PRKN Mutations.

BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society.

Clinical and neuroimaging phenotypes of genetic parkinsonism from infancy to adolescence.

Genetic early-onset parkinsonism presenting from infancy to adolescence (≤21 years old) is a clinically diverse syndrome often combined with other hyperkinetic movement disorders, neurological and imaging abnormalities. The syndrome is genetically heterogeneous, with many causative genes already known. With the increased use of next-generation sequencing in clinical practice, there have been novel and unexpected insights into phenotype-genotype correlations and the discovery of new disease-causing genes. It is now recognized that mutations in a single gene can give rise to a broad phenotypic spectrum and that, conversely different genetic disorders can manifest with a similar phenotype. Accurate phenotypic characterization remains an essential step in interpreting genetic findings in undiagnosed patients. However, in the past decade, there has been a marked expansion in knowledge about the number of both disease-causing genes and phenotypic spectrum of early-onset cases. Detailed knowledge of genetic disorders and their clinical expression is required for rational planning of genetic and molecular testing, as well as correct interpretation of next-generation sequencing results. In this review we examine the relevant literature of genetic parkinsonism with ≤21 years onset, extracting data on associated movement disorders as well as other neurological and imaging features, to delineate syndromic patterns associated with early-onset parkinsonism. Excluding PRKN (parkin) mutations, >90% of the presenting phenotypes have a complex or atypical presentation, with dystonia, abnormal cognition, pyramidal signs, neuropsychiatric disorders, abnormal imaging and abnormal eye movements being the most common features. Furthermore, several imaging features and extraneurological manifestations are relatively specific for certain disorders and are important diagnostic clues. From the currently available literature, the most commonly implicated causes of early-onset parkinsonism have been elucidated but diagnosis is still challenging in many cases. Mutations in ∼70 different genes have been associated with early-onset parkinsonism or may feature parkinsonism as part of their phenotypic spectrum. Most of the cases are caused by recessively inherited mutations, followed by dominant and X-linked mutations, and rarely by mitochondrially inherited mutations. In infantile-onset parkinsonism, the phenotype of hypokinetic-rigid syndrome is most commonly caused by disorders of monoamine synthesis. In childhood and juvenile-onset cases, common genotypes include PRKN, HTT, ATP13A2, ATP1A3, FBX07, PINK1 and PLA2G6 mutations. Moreover, Wilson's disease and mutations in the manganese transporter are potentially treatable conditions and should always be considered in the differential diagnosis in any patient with early-onset parkinsonism.

Successful treatment of psychosis in a patient with Kufor-Rakeb syndrome with low dose aripiprazole: a case report.

We present a case of a 32-year-old male with Kufor-Rakeb syndrome (KRS), a form of juvenile parkinsonism due to mutations of the ATP13A2 gene at PARK9 locus. The patient was seen for daily behavioral outbursts and psychotic symptoms. At first assessment, CGI scale was estimated at 5; "Markedly ill". Aripiprazole was started at 2 mg and then increased to 3 mg. Two years later, psychotic symptoms were judged to be "much improved" (CGI-C = 2). This significant improvement without drug-induced motor side effects suggests that aripiprazole at low doses (2-5 mg) is effective and tolerated in patients with KRS.

DBS in pediatric patients: institutional experience.

INTRODUCTION: DBS is initially used for treatment of essential tremor and Parkinson's disease in adults. In 1996, a child with severe life-threatening dystonia was offered DBS to the internal globus pallidus (GPi) with lasting efficacy at 20 years. Since that time, increasing number of children benefited from DBS. PATIENTS AND METHODS: We retrospectively evaluated our database of patients who underwent DBS from 2011 to 2017. All patients ≤ 17 years of age at the time of implantation of DBS were included in this series. Subjective Benefit Rating Scale (SBRS), Hoehn Yahr Scale (HYS), Fahn Marsden Rating Scale (FMRS), Clinical Global Impressions Scales (CGI), and Yale Global Tic Severity Scale (YGT) were used to evaluate clinical outcome. RESULTS: Between May 2014 and October 2017, 11 children underwent DBS procedure in our institution. Six of them were female and five of them were male. Mean age at surgery was 11.8 ± 4.06 years (range 5-17 years). In our series, four patients had primary dystonia (PDY) (36.3%), three patients had secondary dystonia (SDY) (27.2%), two patients had JP (18.1%), and two patients had Tourette Syndrome (TS) (18.1%). Two JP patients underwent bilateral STN DBS while the other nine patients underwent bilateral GPi DBS. SBRS scores were 1.75 ± 0.5 for patients with PDY, 3 ± 0 for patients with JP, 2.5 ± 0.7 for patients with TS, and 2 ± 1 for patients with SDY. Mean FMRS reduction rate was 40.5 for patients with dystonia. Significant improvement was also defined in patients with TS and JP after DBS. None of the patients experienced any intracerebral hemorrhage or other serious adverse neurological effect related to the DBS. Wound complications occurred in two patients. CONCLUSION: There are many literatures that support DBS as a treatment option for pediatric patients with medically refractory neurological disorders. DBS has replaced ablative procedures as a treatment of choice not only for adult patients, but also for pediatric patients. Wound-related complications still remain the most common problem in pediatric patients. Development of smaller and more flexible hardware will improve quality of children's life and minimize wound-related complications in the future.

A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification.

OBJECTIVES: Mutations in RAB39B have been reported as a potential cause of X-linked Parkinson's disease (PD), a rare form of familial PD. We conducted a genetic analysis on RAB39B to evaluate whether RAB39B mutations are related to PD in the Chinese population. METHODS: In this study, 2 patients from an X-linked juvenile parkinsonism pedigree were clinically characterized and underwent whole-exome sequencing. A comprehensive screening for RAB39B mutations in 505 sporadic patients with PD and 510 healthy controls in a Chinese population was also performed. RESULTS: A novel mutation, c. 536dupA (p.E179fsX48), in RAB39B was identified in the juvenile parkinsonism pedigree. Brain MRI and CT scans in the 2 patients revealed calcification within the bilateral globus pallidus. No other potentially disease-causing RAB39B mutations were found in sporadic PD patients and controls. CONCLUSIONS: X-linked juvenile parkinsonism could be caused by a RAB39B mutation, and basal ganglia calcification may be a novel clinical feature of RAB39B-related parkinsonism. © 2016 International Parkinson and Movement Disorder Society.

Accelerometer based analysis of gait initiation failure in advanced juvenile parkinsonism: a single subject study.

[Purpose] This study used an accelerometer placed close to the center of gravity to quantitatively investigate whether unexpected gait initiation aggravates start hesitation (freezing of gait in gait initiation). [Subject and Methods] The subject was a 53-year-old female who had been suffering from juvenile parkinsonism since she was aged 21 years. An alternating-treatment design was used to compare acceleration characteristics under two gait initiation conditions, which were 1) deliberate gait initiation and 2) gait initiation on a sudden "go" verbal command (sudden gait initiation), in the "on" state of the medication cycle. [Results] In six out of eight sessions, a combination of reduced peak positive anterior accelerations and large power percentage in the high frequency band was consistently observed in the sudden gait initiation compared with deliberate gait initiation. In the other two sessions, although a large acceleration just after the "go" signal was observed, subsequent acceleration signals were blocked by sudden gait initiation. [Conclusion] The results suggest that, even in the "on" state, start hesitation is apparent without increased reliance on frontal cortical attentional mechanisms to compensate for impaired automaticity. In advanced juvenile parkinsonism, sudden gait initiation may be an effective paradigm as a provoking test for start hesitation.

Relevance of Fluorodopa PET Scan in Dopamine Responsive Dystonia and Juvenile Parkinsonism: A Systematic Review.

BACKGROUND: Dopamine Responsive Dystonia (DRD) and Juvenile Parkinsonism (JP) are two diseases commonly presenting with parkinsonian symptoms in young patients. Current clinical guidelines offer a diagnostic approach based on molecular analysis. However, developing countries have limitations in terms of accessibility to these tests. We aimed to assess the utility of imaging equipment, usually more available worldwide, to help diagnose and improve patients' quality of life with these diseases. METHODS: We performed a systematic literature review in English using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and meta-analysis of observational studies in epidemiology (MOOSE) protocols. We only used human clinical trials about dopamine responsive dystonia and juvenile parkinsonism patients in which a fluorodopa (FD) positron emission tomography (PET) scan was performed to identify its use in these diseases. RESULTS: We included six studies that fulfilled our criteria. We found a clear pattern of decreased uptake in the putamen and caudate nucleus in JP cases. At the same time, the results in DRD were comparable to normal subjects, with only a slightly decreased marker uptake in the previously mentioned regions by the FD PET scan. CONCLUSIONS: We found a distinctive pattern for each of these diseases. Identifying these findings with FD PET scans can shorten the delay in making a definitive diagnosis when genetic testing is unavailable, a common scenario in developing countries.

DNAJC6 mutation causing cranial-onset dystonia with tremor dominant levodopa non-responsive parkinsonism: A novel phenotype.

DNAJC6 mutation causes two types of phenotypes: slowly progressive parkinsonism with levodopa response and rapidly progressive parkinsonism with additional manifestations like intellectual disability, epilepsy etc. We report a new phenotype wherein an adolescent girl developed blepharospasm followed by jaw opening, lingual and cervical dystonia followed by tremors of limbs (rest and action) with rigidity, bradykinesia. The dystonia-parkinsonism phenotype has not been described. She had novel homozygous missense mutation in DNAJC6 gene.

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings.

Parkinson disease (PD) is a complex neurodegenerative disorder, usually with multifactorial etiology. It is characterized by prominent movement disorders and non-motor symptoms. Movement disorders commonly include bradykinesia, rigidity, and resting tremor. Non-motor symptoms can include behavior disorders, sleep disturbances, hyposmia, cognitive impairment, and depression. A fraction of PD cases instead is due to Parkinsonian conditions with Mendelian inheritance. The study of the genetic causes of these phenotypes has shed light onto common pathogenetic mechanisms underlying Parkinsonian conditions. Monogenic Parkinsonisms can present autosomal dominant, autosomal recessive, or even X-linked inheritance patterns. Clinical presentations vary from forms indistinguishable from idiopathic PD to severe childhood-onset conditions with other neurological signs. We provided a comprehensive description of each condition, discussing current knowledge on genotype-phenotype correlations. Despite the broad clinical spectrum and the many genes involved, the phenotype appears to be related to the disrupted cell function and inheritance pattern, and several assumptions about genotype-phenotype correlations can be made. The interest in these assumptions is not merely speculative, in the light of novel promising targeted therapies currently under development.

Juvenile Parkinsonism with PARK2 Gene Mutation Misdiagnosed as Dopa-responsive Dystonia: a Case Report.

Parkinson's disease is prevalent in elderly patients, usually aged over 50 years. If clinical symptoms of parkinsonism appear before 21 years of age, it is called juvenile parkinsonism (JP). JP may present atypical features such as dystonia, and is often misdiagnosed as other diseases, including dopa-responsive dystonia (DRD). Here, we report a case of JP with PARK2 mutation misdiagnosed as DRD. A 32-year old female, who presented dystonia of both legs, was initially diagnosed with hereditary spastic paraplegia and showed a dramatic response to low-dose L-dopa, which led to the diagnosis of DRD. However, Parkinson's disease caused by a mutation in the PARK2 gene was later diagnosed via next-generation sequencing. Accurate understanding of JP is necessary for early diagnosis and comprehensive management of movement disorders at a young age.

Neuronal Intranuclear Inclusion Disease: Longitudinal Case Report of Motor and Nonmotor Symptoms.

Neuronal intranuclear inclusion disease is a rare, neurodegenerative disorder with onset in childhood. We report a single case natural history over 10 years and present a review of juvenile parkinsonism and neuronal intranuclear inclusion disease. Our patient was initially seen at the University of Rochester at age 12 years after 4 years of progressive dysarthria, dysphagia, and clumsiness. His neurologic examination was notable for parkinsonism. He had excellent initial response to levodopa, but subsequently developed dopa-induced motor fluctuations, dyskinesias, psychosis, and dystonia. Later in the course, he developed multiple nonmotor symptoms and ultimately died from respiratory failure. Neuropathology demonstrated large eosinophilic nuclear inclusions and small ubiquitin-related modifier 1 (SUMO-1) immunoreactivity, confirming the diagnosis of neuronal intranuclear inclusion disease. This diagnosis should be considered in a patient presenting with juvenile parkinsonism. Clues to the diagnosis include early-onset dopa-induced dyskinesias, gastrointestinal dysfunction, and oculogyric crises.

Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.

BACKGROUND: Phosphoglycerate kinase-1 deficiency is caused by X-linked recessive mutations in PGK-1 and associated with haemolytic anaemia, rhabdomyolysis, myopathy and nervous system involvement. Some cases have been rarely associated with juvenile Parkinsonism however the causal relationship between PGK1 deficiency and nigrostriatal dysfunction causing Parkinsonism has not been determined. OBJECTIVE AND METHODS: To investigate the nigrostriatal system using 99mTc-TRODAT-1 SPECT binding and report the phenotype of three affected males with early onset levodopa responsive Parkinsonism harbouring the c.491 A > T/p.D164V pathogenic variant. RESULTS: All patients initially presented with infantile-onset encephalopathic and stroke-like episodes, haemolytic anaemia and epilepsy. Two patients had an early-onset and one juvenile-onset levodopa responsive Parkinsonism with motor fluctuations. 99mTc-TRODAT-1 SPECT showed severe bilateral reduced putaminal uptake in the three patients. None of the patients had structural lesions that could explain either pre- or postsynaptic dopaminergic dysfunction. CONCLUSION: These cases provide strong evidence of a causal relationship between PGK1 deficiency and nigrostriatal pathology causing Parkinsonism. These findings have potential implications for our understanding of the pathophysiology of nigrostriatal degeneration in sporadic PD.

Juvenile parkinsonism: Differential diagnosis, genetics, and treatment.

Juvenile parkinsonism is arbitrarily defined as parkinsonian symptoms and signs presenting prior to 21 years of age. Levodopa-responsive juvenile parkinsonism that is consistent with diagnostic criteria for Parkinson's disease is most often caused by mutations in the PARK-Parkin, PARK-PINK1, or PARK-DJ1 genes. However, many other genetic and acquired parkinsonian disorders presenting in childhood or young adulthood are being reported, often with atypical features, such as presence of other movement disorders, cognitive decline, and psychiatric symptoms. The genetic landscape of juvenile parkinsonism is rapidly changing with the discovery of new genes. Although the mainstay of treatment remains levodopa, other symptomatic therapies such as botulinum toxin for focal dystonia, supportive medical therapies, and deep brain stimulation in select cases, may also be used to provide the most optimal long-term outcomes. Since the topic has not been reviewed recently, we aim to provide an update on genetics, differential diagnosis, evaluation, and treatment of juvenile parkinsonism.

Investigation of the Treatment and Living Assistance Needed by Patients with Young-Onset Parkinson's Disease.

PURPOSE: This study assessed the symptoms, treatment, social systems use, and perception of living conditions of patients with young-onset Parkinson's disease (YOPD), and investigated the support needed by them. METHOD: Among the 252 people who completed our questionnaire, we defined YOPD patients as those diagnosed as young onset or those with onset at ≤40 years. The data were compared with others. RESULTS: There were 24 patients with YOPD (9.5%) (average age: 61.7 years), with an average disease duration 6.4 years longer (p < 0.01) and time until diagnosis 0.7 years longer (p < 0.1) than those of other patients. This group took 1.6 times more types of medicines, and time to their next appointment was 8.6 days shorter than that of other patients (p < 0.05). Patients with YOPD had more pulsive walking and more sweating (p < 0.05), and more motor fluctuation (p < 0.1). More patients with YOPD had a physical disability certificate but felt they were not obtaining the required services (p < 0.05). 45.0% of the YOPD group wanted to work more, more used information and communication equipment (p < 0.05), and more felt their medications were adequate (p < 0.1). CONCLUSIONS: Increased awareness of YOPD is needed. YOPD patients have motor fluctuation because of the longer disease duration. Thus, the support of doctors and nurses, and frequent examination visits, are indispensable for controlling symptoms to achieve middle age developmental tasks. Increased support for care-giving, leisure-time activities, and work is also necessary and may help maintain the desire to work in this group.

Parkinsonian-Pyramidal syndromes: A systematic review.

INTRODUCTION: Parkinsonian-Pyramidal syndrome (PPS), defined as the combination of both pyramidal and parkinsonian signs is a concept that recently emerged. PPS may manifest itself in numerous neurodegenerative diseases, many of these being inherited. Their diagnosis is a major challenge for the clinical management, for the prognosis, for genetic counselling and, in a few cases, which should not be neglected, for specific treatment. OBJECTIVE: Our objective is to provide a review of PPS and an algorithm in order to guide their diagnosis in clinical practice. METHODS: We performed an exhaustive PubMed and OMIM research matching the following key words: "Parkinsonism and pyramidal signs" or "Parkinsonism and spasticity" or "pallido-pyramidal syndrome" or "Parkinsonism and spastic paraplegia". English publications from the last ten years were included. RESULTS: We propose a pragmatic presentation based on several established classifications and we will distinguish inherited PPS found in complex hereditary spastic paraplegia, young onset parkinsonism, neurodegeneration with brain iron accumulation, primary familial brain calcifications, inborn errors of metabolism, and few rare others inherited neurodegenerative diseases, then non-inherited neurodegenerative PPS. We therefore suggest guidelines (based on age at onset, family history, associated clinical signs, brain MRI findings as well as certain laboratory investigations), for the diagnosis and the management of PPS. Many pathophysiological pathways may underlie PPS but the most frequent are those usually involved in both inherited Parkinson's disease and spastic paraplegia, i.e. mitochondrial pathway, vesicular trafficking including endosomal and lysosomal pathways as well as autophagy.