Genotype-phenotype relations for episodic ataxia genes: MDSGene systematic review.

BACKGROUND: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms. METHODS: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/). RESULTS: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'. CONCLUSION: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

Levodopa-Carbidopa Intestinal Gel for Parkinson's Disease over 11 years: One Center's "Real-World" Experience.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) therapy has been shown to be a safe and effective treatment for advanced Parkinson's disease (PD). Limited data are available regarding long-term benefits and complications in Canada. Objective of the study was to review long-term experience and clinical outcomes in PD patients with LCIG therapy over 11 years in a multidisciplinary University clinic setting. METHODS: Chart review was done on PD patients with LCIG from 2011 to 2022. Data collected: dosing, UPDRS-III motor scores, OFF times, hours with dyskinesias, MoCA, complications, discontinuation reasons, and nursing time requirements. RESULTS: Thirty-three patients received LCIG therapy with a mean follow-up of 3.25±2.09 years. UPDRS-III scores showed reduction of 15% from baseline (mean 35.9) up to 4 years (mean 30.4). Daily OFF time improved from baseline (mean 7.1 ± 3.13 hours) up to 5 years (mean 3.3 ± 2.31 hours; -53.5%; p < 0.048), and dyskinesias remained stable. Nursing time averaged 22 hours per patient per year after PEG-J insertion and titration. Most common complications were PEG-J tube dislodgement and stoma site infection (0-3zero to three events/patient/year). Serious side effects were seen in four (12%) patients resulting in hospitalization and/or death. Nine patients (27.2%) discontinued the treatment due to lack of improved efficacy over oral therapy or development of dementia and 10 (30%) died of causes unrelated to LCIG infusion. CONCLUSION: Patients on LCIG showed improved motor function over 5-year follow-up. Serious complications were uncommon. Dedicated nursing time is required by LCIG-trained nurses in a multidisciplinary setting for optimum management.

Dystonia and Parkinson's disease: What is the relationship?

Dystonia and Parkinson's disease are closely linked disorders sharing many pathophysiological overlaps. Dystonia can be seen in 30% or more of the patients suffering with PD and sometimes can precede the overt parkinsonism. The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is variable; dystonia commonly occurs in PD patients following levodopa initiation. Similarly, parkinsonism is commonly seen in patients with mutations in various DYT genes including those involved in the dopamine synthesis pathway. Pharmacological blockade of dopamine receptors can cause both tardive dystonia and parkinsonism and these movement disorders syndromes can occur in many other neurodegenerative, genetic, toxic and metabolic diseases. Pallidotomy in the past and currently deep brain stimulation largely involving the GPi are effective treatment options for both dystonia and parkinsonism. However, the physiological mechanisms underlying the response of these two different movement disorder syndromes are poorly understood. Interestingly, DBS for PD can cause dystonia such as blepharospasm and bilateral pallidal DBS for dystonia can result in features of parkinsonism. Advances in our understanding of these responses may provide better explanations for the relationship between dystonia and Parkinson's disease.

CAPN1 mutations: Expanding the CAPN1-related phenotype: From hereditary spastic paraparesis to spastic ataxia.

AIMS AND OBJECTIVE: To characterize the phenotype of CAPN1 (SPG76) mutations in patients diagnosed with hereditary spastic paraplegia (HSP). BACKGROUND: The CAPN1 gene, located on chromosome 11q13.1, is a protein-coding gene involved in neuronal plasticity, migration, microtubular regulation and cerebellar development. Several families with CAPN1 mutations have recently been reported to present with autosomal recessive (AR) HSP and/or ataxia. METHOD: Patients with HSP were identified through neurological and genetic clinics with detailed phenotyping. Whole exome sequencing revealed novel pathogenic CAPN1 mutations in four patients from 3 families. RESULTS: Affected families were of Turkish, Japanese, and Punjabi descent and all were consanguineous. Onset of spastic paraplegia in the four patients was between 20 and 37 years. Two also had mild ataxia. Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy). CONCLUSIONS: The phenotype of AR CAPN1 mutations appears to be spastic paraplegia with or without ataxia; onset is most commonly in adulthood. Eye movement abnormalities, skeletal defects, peripheral neuropathy and amyotrophy can sometimes be seen. Occasionally, patients can present with ataxia, illustrating the genotypic and phenotypic overlap between HSP and spastic ataxia. With the advent of exome sequencing, mutations in more than one gene can be identified, which may contribute to the phenotypic variation, even within a family.

Ophthalmoplegic migraine with isolated third cranial nerve palsy in a known case of juvenile myoclonic epilepsy.

Among the various forms of migraine headaches, ophthalmoplegic migraine is an uncommon and rare form, the incidence of which is approximately 0.7 per million. It presents predominantly with headache and ophthalmoplegia. One of more cranial nerves can be affected, however the third cranial nerve is most often affected. As a result, symptoms wise, mydriasis and ptosis are commonly seen. Patients generally recover completely within a few days or weeks, however residual deficits are known to occur in a minority of patients. One of the common generalised epilepsy syndromes is the juvenile myoclonic epilepsy (JME), its prevalence being roughly up to 10% of all patients with epilepsy. It usually begins in the second decade of life. Generalised tonic-clonic seizures myoclonic jerks absences constitute the main seizure types in JME. Studies indicate a definite association of epilepsy with migraine headaches and a significant number of migraneurs are found to be epileptic. Conversely, patients with epilepsy are two times more likely to have migraine, as compared to their first degree relatives without migraine. We report a known case of a female patient of JME having a history of classical migraine with aura presenting to us with headache and ophthalmoplegia. She was extensively evaluated to rule out other causes of isolated third cranial nerve palsy, with all the investigations being negative for any obvious cause. She was treated with non-steroidal anti-inflammatory drugs for the acute attack and was subsequently put on antimigraine medication, propranolol during her hospital stay, with which her ptosis recovered completely after 2 weeks. The patient was later started on tablet divalproex sodium, which the patient continues to take on a long-term basis, especially because of its efficacy as an antimigraine prophylaxis agent and a potent drug against JME.