A 30-year-old right-handed man was born at term with mildly delayed developmental milestones. In childhood, he developed progressive blurred vision, and in his teens he developed constipation, right-hand rest tremor, and muscle atrophy. At age 20, he collapsed while running and had myoglobinuria. Progressively slower gait, stooped posture, and falls eventually required him to use assistance walking. He also developed nocturnal drooling, micrographia, urinary incontinence, generalized myalgia, and paresthesias. His elder sister and mother had mild exercise intolerance, but no parkinsonism, and are likely heterozygous for the X-linked gene.
At age 26 (see Video, Segment 1), he had hypomimia, hypophonia, right-hand rest tremor, mild weakness in the right iliopsoas and hamstrings, and asymmetric, right predominant parkinsonism. He rose slowly from a chair unassisted, but had a slow shuffling gait with freezing, en-bloc turning, and imbalance. l-dopa was started, but he developed irritability, paranoia, sexually inappropriate behavior, and visual hallucinations at 600 mg/day, which resulted in incarceration for a brief period. The psychosis was not responsive to quetiapine at 100 mg/day, but improved when l-dopa was discontinued and quetiapine was maintained.
He was lost to follow-up for a few years and, when observed again at age 29, he had progressive functional decline and was primarily confined to a wheelchair. He was unable to perform fine finger movements on the right, had to push to stand, and had a slow, shuffling gait. At age 30, clozapine was added to his regimen in order to reinstitute l-dopa therapy because, on clozapine 100 mg/day and quetiapine 200 mg/day, he continued to have severe rigidity and bradykinesia on the right, required assistance to stand, and was completely frozen when attempting to walk (see Video, Segment 2).
l-dopa was reinitiated and—over 4 weeks—titrated to 800 mg/day with consistent daily improvement in his parkinsonism. His voice was louder, his face showed spontaneous expression, and his right-sided bradykinesia and rigidity were markedly improved (see Video, Segment 3). He was also able to stand and walk without assistance, but his imbalance, though improved, persisted. During the titration, he developed irritability, which led to decreasing l-dopa to 700 mg/day and increasing clozapine to 125 mg/day without significant decline in function. However, over the subsequent months, he also developed inappropriate behaviors toward family members and friends and his caregiver stopped his l-dopa. He is in the process of very slowly titrating back up on the l-dopa after further increase in his antipsychotic agents to determine the lowest effective dose of Sinemet where psychosis can also be suppressed.
A 24-year-old right-handed man was born at term with normal developmental milestones. At age 7, he developed progressive weakness, paroxysmal muscle cramping, and required two intensive care unit hospitalizations for exercise-induced rhabdomyolysis. At age 19, left-hand rest tremor appeared. Over the next 2 years, he gradually developed rigidity, generalized asymmetric bradykinesia, hypomimia, hypophonia, progressively slower gait with a stooped posture, and dysphagia. Behavior and cognition remained intact.
By age 21, he was slow with all his activities of daily living, required assistance cutting food, and was noted by his father to be depressed. l-dopa was initiated with decreased tremor and improved mobility at 125 mg/day. Increasing the dosage to 250 mg/day led to severe dyskinesias and subsequent rhabdomyolysis within 3 days, leading to hospitalization and discontinuation.
At age 21, he had left-hand rest and action tremor, asymmetric left predominant parkinsonism, ability to rise from a chair unassisted, slow shuffling gait without freezing, en-bloc turning, and positive pull test. Pramipexole was slowly initiated over a period of months (without knowledge of the response of patient 1 to treatment) with improved tremor, rigidity, bradykinesia, gait, and postural reflexes starting at 3 mg/day. However, 6 weeks after achieving a dose of 4.5 mg/day, he developed obsessive shopping, sexually inappropriate behaviors, and restlessness, which improved with decreased doses (2 mg/day), but compromised his motor function. As a result of the positive motor benefit achieved with pramipexole, the patient and his family did not want to discontinue dopaminergic treatment, but were willing to try a different agent to see whether similar side effects occurred. Unfortunately, on 1.5 mg/day ropinirole, he had similar behavioral effects. Addition of l-dopa 100 mg/day to low-dose agonist caused increased restlessness, irritability, and “irrational behavior” and was discontinued after 1 week. He continues treatment with pramipexole 3 mg/day with continued obsessive shopping and sexually inappropriate behavior. He also has continued slow motor decline, with increased difficulty swallowing and walking, at age 24. However, after long refusal, he has finally agreed to begin treatment with an antipsychotic agent, although this has not been instituted as yet.