Levodopa Responsive Parkinsonism in Two Patients With Phosphoglycerate Kinase Deficiency

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Authors: Tuhin Virmani, Michael Rotstein, Ronen Spiegel, Hasan O. Akman, Salvatore DiMauro and Paul E. Greene

Article first published online: 26 JUN 2014 | DOI: 10.1002/mdc3.12055

Although human phosphoglycerate kinase (PGK) is a ubiquitous enzyme, deficiency states have only manifested clinically with involvement of the central nervous system (CNS; mental retardation, behavioral abnormalities, seizures, and parkinsonism), skeletal muscle (exercise intolerance, cramps, and myoglobinuria), or erythrocytes (hereditary nonspherocytic hemolytic anemia).[1] Whereas hemolytic anemia alone, myopathy alone, and anemia with CNS involvement account for most reported cases,[1] only 5 published cases showed a combination of CNS and skeletal muscle involvement.[2-6] CNS involvement in these 5 cases included 2 patients with mental retardation,[2, 5] 2 with mental retardation and epilepsy,[5] and 1 with parkinsonism (patient 1 below).[3] One patient has also been reported with myopathy and retinitis pigmentosa.[6] A sixth patient, previously reported to have myopathy alone,[1] later developed parkinsonism (patient 2).

Both our patients with early-onset parkinsonism and myopathy had decreased PGK activity and a hemizygous, X-linked, p.T378P mutation in the PGK1 gene.[1, 3] Here, we show that their parkinsonism was responsive to levodopa.


Case Reports

Patient 1

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.

Patient 2

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.


Here, we document 2 cases of l-dopa-responsive parkinsonism, in 2 unrelated young men with identical hemizygous X-linked mutations in PGK1. Interestingly, a report from 1973 documented 2 brothers with PGK deficiency, nonspherocytic hemolytic anemia, developmental delay, and generalized tremor, which worsened with action and was not improved with trihexyphenidyl or l-dopa.[7] Molecular analysis was not available at the time to determine what mutation they harbored.

Early psychosis limited treatment in both patients and should be closely monitored when treating other patients with this disorder. The use of high-dose clozapine and quetiapine helped improve the psychosis when started before initiation of l-dopa, but delayed psychosis still occurred with l-dopa titration over weeks. Because these patients were significantly debilitated from the motor manifestations of their parkinsonism, which are progressive (as seen in the Video), it seemed reasonable to still attempt dopaminergic therapy. However, pretreatment with antipsychotics are likely warranted, patients should be aware of the significant manifestations of the psychosis, and their families should be instructed on how to monitor for it. Based on this limited experience, a very slow titration of l-dopa, over a period of several months rather than weeks, could be attempted while monitoring for the delayed development of psychosis and treating it aggressively. Given that the patients are dopamine responsive, DBS surgery may be an option to help the motor symptoms while minimizing the dose of l-dopa. This, however, remains a theoretical possibility.

Because both these patients have the same mutation in PGK1, a male patient with evidence of myopathy and parkinsonism should be tested for this mutation before initiation of l-dopa therapy. How a deficiency in PGK may predispose to early development of psychosis with l-dopa is unclear because PGK plays a role in generation of adenosine triphosphate during glycolysis. Whether PGK1 deficiency predisposed these men to early-onset parkinsonism by interfering with a common regulatory pathway remains to be seen. The small numbers of patients with this disorder and the high heterogeneity of clinical presentation make it difficult to establish any such links.



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