Supplementary Material for: Long-Term Follow-Up with Video of a Patient with Deafness-Dystonia Syndrome Treated with DBS-GPi

<p><b><i>Background:</i></b> The prevalence of deafness-dystonia syndrome (DDS) is relatively low. To our knowledge, only 2 cases of this syndrome treated with deep brain stimulation (DBS) have been reported. <b><i>Objectives:</i></b> We present a patient with DDS of unknown cause, refractory to medical treatment, who has been successfully treated with DBS of the internal globus pallidus (DBS-GPi) and followed up for 4 years. <b><i>Methods:</i></b> A 21-year-old male, with progressive bilateral sensorineural hearing loss since the age of 3, developed dystonic movements at the age of 12. The patient presented with progressive segmental craniocervical dystonia with jaw-opening, tongue protrusion, retrocollis and gradual overflow including upper limb dystonia. Pharmacological therapy was ineffective. At the age of 17, the patient's condition deteriorated with the risk of developing a dystonic state. <b><i>Results:</i></b> DBS-GPi implantation resulted in a striking improvement. The Burke-Marsden-Fahn Dystonia Rating Scale (BMFDRS) score improved from 75 points before the surgery to 10 points at 3 months after DBS-GPi implantation. Neurological examination at the age of 21 showed mild dystonic movements, mainly oromandibular dystonia (BMFDRS: 15 points). The clinical phenotype of our patient was consistent with Mohr-Tranebjaerg syndrome (MTS). We performed genetic analysis of the <i>TIMM8A</i> gene (the only gene in which mutations are known to cause MTS), but the result was negative; however, other potentially new mutations have to be considered. <b><i>Conclusions:</i></b> Based on our case with the longest reported follow-up of 4 years and 2 earlier reports, we advise to consider DBS-GPi in patients with DDS with unsatisfactory effect of pharmacological treatment.</p

Clinical variability of neuroacanthocytosis syndromes : A series of six patients with long follow-up

Objective To provide clinical clues to differential diagnosis in patients with chorea and other movement disorders with blood acanthocytes. Methods We present a long-term video accompanied follow-up of six Caucasian patients with neuroacanthocytosis from several centers, three diagnosed with chorea-acanthocytosis (ChAc): 34-y.o.(no.1), 36-y.o.(no.2), 43-y.o.(no.3), two diagnosed with McLeod Syndrome (MLS): 52-y.o.(no.4), 61-y.o.(no.5) and one 63-y.o.(no.6), a brother of no.5, with clinical suspicion of MLS. Additionally we report pathological findings of the mother of two brothers with MLS reported in our series with acanthocytes on peripheral blood smear Results The patients had an unremarkable family history and were asymptomatic until adulthood. Patients no. 1,2,4,5,6 developed generalized chorea and patient no. 3 had predominant bradykinesia. Patients no. 1,2,3 had phonic and motor tics, additionally patients no. 1 and 2 exhibited peculiar oromandibular dystonia with tongue thrusting. In patients no. 2 and 3 dystonic supination of feet was observed, patient no. 3 subsequently developed bilateral foot drop. Patients no. 2 and 4 had signs of muscle atrophy. Tendon reflexes were decreased or absent and electroneurography demonstrated sensorimotor neuropathy in patients no. 1,2,3,4,5, except no. 6. Generalized seizures were seen in patients no. 2,3,5,6 and myoclonic jerks in patient no. 1. Cognitive deterioration was reported in patients no. 1,2,3,5,6. Serum creatine kinase levels were elevated in all six patients. Conclusion We highlight the variability of clinical presentation of neuroacanthocytosis syndromes and the long time from the onset to diagnosis with the need to screen the blood smears in uncertain cases, however, as in one of our cases acanthocytes may even be not found. Based on our observations and data from the literature we propose several red flags that should raise the suspicion of an NA syndrome in a patient with a movement disorder: severe orofacial dyskinesia with tongue and lip-biting (typical of ChAc), feeding dystonia, psychiatric and cognitive disturbances, seizures, peripheral neuropathy, elevation of creatine kinase, elevation of transaminases, hepatosplenomegaly, cardiomyopathy and arrhythmias, and an X-linked pattern of inheritance (McLeod Syndrome, MLS)

Leucine-rich repeat kinase-2 (LRRK2) R1441G knockin mice are more susceptible to rotenone toxicity

This journal suppl. entitled: Supplement: Abstracts of the Eighteenth International Congress of Parkinson's Disease and Movement Disorders / Poster PresentationOBJECTIVE: To assess the susceptibility of LRRK2 R1441G knockin mice against (1) striatal dopamine (DA) uptake deficit, (2) locomotor inactivity and, (3) dopaminergic neuronal cell death, as induced by rotenone (mitochondrial complex-I inhibitor). BACKGROUND: LRRK2 mutations are the commonest genetic risk in Parkinson's disease (PD). LRRK2 is linked to synapse functions. However, the pathogenic mechanism of LRRK2 mutation in striatal DA homeostasis and mitochondria dysfunction is unknown. METHODS: Cell viability of primary DA neurons from R1441G knockin mice and their wild-type littermates were compared after rotenone exposure. Total [3H]-DA uptake in isolated striatal synaptosomes incubated with rotenone, and the locomotor activity in open-field test after chronic (20 weeks) oral gavage of rotenone were also assessed. RESULTS: Without rotenone, R1441G mutant mice show no overt phenotype. However, synaptosomes from young (3-month-old) mutant mice exhibited lower DA uptake when incubated with rotenone (100nM), compared with wild-type controls. Number of tyrosine hydroxylase (TH)-positive neurons in mutant culture after rotenone exposure (5nM) was significantly lower. Also, chronic exposure to rotenone (5mg/kg, twice per week orally) for 20 weeks caused significantly lower locomotor activity in mutant mice compared with the wild-type controls. CONCLUSIONS: Similar to R1441C [1], LRRK2 R1441G mutant mice show no overt phenotype. However, R1441G mutant synaptosomes were more vulnerable to rotenone toxicity as shown by lower DA uptake, indicating that R1441G mutation contributes to mitochondrial dysfunction-induced synaptic dysfunction. Re-uptake of extracellular DA requires mitochondrial ATP for synaptic recycling. Uptake deficits associated with LRRK2 mutation may adversely affects striatal neuronal survival and locomotor activity as observed in our mutant mice. This differential susceptibility against rotenone toxicity of the mutant mice suggests that LRRK2 R1441G mutation may be a predisposing genetic factor in synaptic energy deficiency leading to early striatal synaptic dysfunction [2], and later nigrostriatal DA cell death in LRRK2-associated PD.link_to_OA_fulltex

A Randomized, Double-blind, Placebo-Controlled Study of Latrepirdine in Patients With Mild to Moderate Huntington Disease

Experimentele farmacotherapi