Chronic Progressive Ataxia Research Articles

Diagnosis of lymphoma based on magnetic resonance imaging, analysis of cerebrospinal fluid, intraocular fluid and fine‐needle aspirate of a uveal mass lesion in a dog

AbstractA 10.5‐year‐old, male, entire labrador retriever dog was presented for chronic progressive ataxia and recent onset of a left‐sided head tilt and salivation. Neurological examination findings were deemed consistent with a multifocal brain and spinal cord neuroanatomic localisation. Ophthalmological examination of the right eye revealed pupil shape abnormality (dyscoria), a pale uveal mass lesion and white cellular sediment in the anterior chamber. Magnetic resonance imaging of the brain, eyes, thoracolumbar and lumbosacral spinal cord and surrounding structures showed multiple lesions affecting the central nervous system (brain), peripheral nervous system (left trigeminal nerve) and right eye. Cerebrospinal fluid, right eye anterior chamber fluid and fine‐needle aspirate biopsy of the uveal mass lesion yielded a cytological diagnosis of lymphoma (suspected large granular lymphocytic). The dog was discharged with palliative treatment and euthanased at home 4 days later. This case report documents the cytological diagnosis of lymphoma in the cerebrospinal fluid, intraocular fluid and fine‐needle aspirate of a uveal mass in a dog.

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia. We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23cells and cultured neurons. Variants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

Patient-Friendly Summary of the ACR Appropriateness Criteria®: Ataxia-Child

Not being able to move in a coordinated fashion is referred to as ataxia. Signs of ataxia include clumsiness, unsteady gait, nystagmus, and dysdiadochokinesis (inability to perform rapid alternating movements like foot tapping). Ataxia may be genetic or acquired, such as from illness or trauma. Acute onset ataxia develops within hours or days. In children with acute ataxia and no recent history of trauma, MRI head without and with contrast, MRI head without contrast, or CT head without contrast are usually appropriate. MRA head and/or neck, MRI spine, and CTA head and/or neck may be appropriate. For acute ataxia (following traumatic head or neck injury), MRI head without contrast or CT head without contrast are usually appropriate. MRA head and/or neck and CTA head and/or neck may be appropriate. For recurrent ataxia (episodes of ataxia followed by relatively symptom-free periods), MRI head without contrast is usually appropriate. MRI spectroscopy head or MRI head without and with contrast may be appropriate. For chronic progressive ataxia (symptoms typically appear and increase in severity over at least two months), MRI head without and with contrast or MRI head without contrast are usually appropriate. MRI complete spine without or with/without contrast, and CT head without contrast may be appropriate. For chronic nonprogressive ataxia (symptoms typically appear in first year of life, last more than two months, and do not change in severity), MRI head without contrast is usually appropriate. MRI complete spine without contrast and CT head without contrast may be appropriate.

Long-Surviving Adult Siblings With Joubert Syndrome Harboring a Novel Compound Heterozygous CPLANE1 Variant.

Background and ObjectivesWe describe 2 long-surviving siblings with a mild phenotype of Joubert syndrome (JBTS) harboring a novel compound heterozygous missense variant in the CPLANE1 gene.MethodsTargeted sequencing data of 2 middle-aged siblings (sister and brother) with JBTS were analyzed.ResultsThe patients were older than 60 years and presented with an inborn facial anomaly and ataxia, accompanied by a molar tooth sign on brain MRI. The male patient showed mild intellectual disability, abnormal eye movements, and progressive gait disturbance. Targeted sequencing revealed a compound heterozygous missense variant of CPLANE1 p.Arg1193Cys_Gln1223Pro; c.3577C>T_3668A>C. Multiple in silico assays predicted that the missense sites were pathogenic.DiscussionThe phenotype-genotype correlation of CPLANE1 remains controversial, although many cases have been previously reported in children and young adults. Our study revealed a novel pathogenic variant of CPLANE1 in patients, confirming the role of this gene in JBTS, thus providing an opportunity for neurologists to recognize JBTS as a differential diagnosis for chronic progressive ataxia in an aging society.

BREAST CANCER ASSOCIATED ANTI YO-ANTIBODY MEDIATED PARANEOPLASTIC CEREBELLAR DEGENERATION: CASE SERIES AND REVIEW OF LITERATURE

Paraneoplastic cerebellar degeneration (PCD) is a rare immune mediated disorder characterized by progressive cerebellar ataxia in presence of onconeural antibodies which occurs due to an indirect effect of underlying malignancy i.e. small cell lung cancer (SCLC), breast and gynecologic cancer, and Hodgkin lymphoma. In about 50% of patients neurological manifestation of Paraneoplastic cerebellar degeneration occurs prior to detection of carcinoma. Anti-Yo Antibody is the commonest antibody present in patients with Paraneoplastic cerebellar degeneration which is associated with breast carcinoma. We describe 3 female patients with anti YO antibody mediated PCD with breast cancer. One patient had a previous diagnosis of breast cancer with post mastectomy status one year back. Two of them presented with ataxia and on further examination, breast lump was found. All three patients had symmetrical ataxia with one patient had severely debilitating ataxia and was not able to walk unassisted. Magnetic resonance imaging brain showed cerebellar atrophy in two patients while one patient had normal MRI. Anti- YO antibody was strongly positive in all the three patients. All patients were given immunotherapy (corticosteroids in 2, Intravenous immunoglobulin in 1) with 1 patient showed modest improvement These case highlights the need to consider for workup for paraneoplastic cerebellar degeneration in female patients presenting with subacute to chronic progressive ataxia, so that the tumors can be detected and treated in early stage with a good outcome.

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia.

Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.

Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia.

Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.

The genetic aetiology of late-onset chronic progressive cerebellar ataxia

An increasing number of dominant and recessive disorders have been associated with late onset chronic progressive ataxia (LOCA) complicating the formulation of a rational diagnostic strategy. Furthermore, there is marked geographic and ethnic variation in the relative importance of these individual disorders and the cause of such observed variation remains unexplained. We have systematically investigated a population-based cohort of patients with chronic progressive LOCA for SCA 1, 2, 3, 6, 7, 8, 10, 12, 17, FXTAS and FRDA. In addition we have examined repeat length polymorphism in chromosomes from a genetically homogeneous and representative control population to investigate the association of high-normal repeats and disease prevalence. A total of 178 patients including 55 familial cases segregating in 38 kindreds and 123 sporadic were investigated. Pathological expansions were identified in 11/38 (28.9 %) of families and in 5/123 (4.1 %) of sporadic patients. The most frequent diagnoses were SCA6 (6 families and 1 sporadic patient), DRPLA (4 families) and SCA8 (1 family). In addition, one elderly female patient was identified with "possible FXTAS". Six (2 %) control patients were noted to have expanded SCA8 alleles. SCA6 and DRPLA were the most frequent genetic diagnoses identified. Patterns of high-normal allele frequency in this UK population were distinct compared to other ethnic groups but this was poorly predictive of the distribution of disease in this region. The relative contribution of new mutation formation and founder effects to the prevalence of familial ataxia is uncertain, and further exploration of these factors will require detailed analysis of disease allele haplotypes and meiotic instability of intermediate length alleles.

A possible variant of neuro-Behçet disease presenting chronic progressive ataxia without mucocutaneo-ocular symptoms

Behçet disease (BD) is a chronic relapsing multisystem disorder of unknown etiology, which preferentially affects the oral and genital mucous membranes, skin, and eyes. Neurological involvement is one of the most serious manifestations of BD, known as neuro-Behçet disease (NBD). We here describe clinical, radiological, and neuropathological findings for two patients with a possible variant of NBD, who manifested progressive ataxia in the absence of mucocutaneo-ocular signs characteristic for BD. Both patients presented a slowly progressive cerebellar phenotype, accompanied by behavioral changes and sphincter disturbance. Brain MRI scan revealed mild atrophy in pons and cerebellum. Both patients showed a mild CSF pleocytosis, and were positive for HLA-B51. The post-mortem examination performed in one patient, showed widespread foci of chronic encephalitis, consistent with the diagnosis of NBD. Steroid pulse therapy was effective in one patient. Identifying the progressive ataxia phenotype of NBD without mucocutaneo-ocular symptoms is important, because these patients may benefit from early steroid therapy.