Alkaptonuria is an ultra-rare (1 in 250,000 to 1 in 1,000,000 incidence) autosomal recessive disease caused by deficient activity of the enzyme homogentisate 1,2-dioxygenase that splits the aromatic ring of homogentisic acid, resulting win an error of catabolism of the aromatic amino acids tyrosine and phenylalanine in the liver.1 This leads to the accumulation of homogentisic acid. Homogentisic acid, a melanin-based polymer, occurs via oxidation of homogentisic acid in the urine, which makes the characteristic black discoloration known as ochronosis.2
Ochronosis, most commonly found in the joints, cardiovascular system, and the liver,3 has also been found in the brain of patients with alkaptonuria.4 Ochronosis can be comorbid with neuroblastoma,5 astrocytoma, and concomitant pituitary adenoma6 with alkaptonuria.
The association of alkaptonuria and Parkinson's disease (PD) has been reported in the literature7–9 and is probably due to ochronotic pigment deposition.10 Proctor7 stated that electron transfer properties of homogentisic acid may cause extrapyramidal symptoms in species that have melanin in substansia nigra. Wilson's disease, manganese poisoning, or phenothiazine-induced parkinsonism are similar electron donor-associated syndromes in humans according to this research, which was published in 1970.7 In the same year, Siekert and Gibilisco8 reported a patient with PD who received another diagnosis—alkaptonuria—when the blue discoloration of her teeth was noticed. A third case of this comorbidity was also reported in the same year, with high urinary excretion of homogentisic acid seen in a patient with PD during treatment with dopamine. This led to the proposal of a new syndrome, known as striatonigral ochronosis.11
In 2011, a 65-year-old patient hospitalized due to PD was also diagnosed with alkaptonuria after developing dark brown urine after treatment with dopamine.9
Although the coexistence of PD and psychiatric symptoms is well known, there are few reports of psychiatric symptoms in alkaptonuria.12,13 To the best of our knowledge, the case presented here is only the fifth case of PD with comorbid alkaptonuria and the first case with additional psychiatric symptoms to be reported in the literature. This article reports on a patient diagnosed with PD and alkaptonuria who developed affective symptoms.
Case Description and Diagnosis
The patient, a 42-year-old woman with a 5-year history of PD, was referred to our psychiatry clinic in April 2018 with complaints of euphoria, aggression, insomnia, and increased sexual activity. Because of the aggression, her family immediately brought her to the hospital where she received a diagnosis of mania and organic affective disorder.
Her first complaints began at age 37 years with tremors in the left hand and leg. She was admitted to the neurology outpatient clinic and was diagnosed with early-onset PD. Various medications such as pramipexole, bornaprine, levodopa, and rasagiline had been prescribed to her but the tremors only worsened with time and she developed urinary incontinence. Three years after her initial presentation, when she was age 40 years, she was prescribed escitalopram for 6 months because of depressive symptoms. One year after that, when the patient was hospitalized in the neurology clinic, genetic tests were performed, and she was diagnosed with alkaptonuria after she told clinicians that she remembered having dark urine during childhood. Cranial magnetic resonance imaging (MRI) and echocardiogram were performed to detect any complications, but no significant pathologic sign was found.
She was discharged with prescriptions for levodopa, carbidopa, entacapone, and ropirinole. Instructions to take vitamin C and adhere to a specific diet were added for the treatment of her alkaptonuria. After a psychiatric consultation, sertraline was added to the patient's treatment because of depressive symptoms and was eventually increased to a dose of 200 mg daily.
Complaints of agitation, insomnia, and excessive spending of money started in October 2017, approximately 6 months prior to her presentation at our clinic. The patient had left home, engaged in random sexual encounters, and physically attacked her family. She had been admitted to many psychiatry outpatient clinics previously and had been prescribed quetiapine at a dose of up to 400 mg daily, but her symptoms did not improve. When the patient was admitted to our psychiatry clinic, she was taking levodopa, carbidopa, and entacapone for her PD and quetiapine for her manic symptoms. Her physical examination was normal and there was no ochronotic pigmentation on her body. A mental state examination revealed tangentiality, loose association, and grandiose and erotomaniac delusions. Prediagnosis of a manic episode secondary to PD or dopaminergic agents was considered. The patient's hemogram, liver functions, kidney functions, and electrocardiogram (ECG) were examined, and all laboratory functions and ECG were normal. There were no pathological findings except for nonspecific gliotic signal changes in cranial MRI. Electroencephalogram was normal. A dopamine transporter scan (DaTscan) was performed to confirm the diagnosis of Parkinson's disease. DaTscan is a single photon emission computed tomography scan of the dopamine transporter and provides information about nigrostriatal degeneration.14 It has been approved by the US Food and Drug Administration for the diagnosis of PD.15 The DaTscan of our patient revealed significant degeneration in the right putamen and the caudate nucleus.
Treatment and Management
The patient's doses of levodopa, carbidopa, and entacapone were slightly reduced because of the possibility that the her symptoms were due to dopaminergic agents. For her manic symptoms, the quetiapine was discontinued, and clozapine was prescribed and increased to a dose of 200 mg per daily. After 1 month of treatment with clozapine her manic symptoms greatly improved. The clozapine was discontinued before her DaTscan due to the possibility that it could affect the results. During follow-up treatment, levodopa and benserazide were added to the treatment after a consultation with the neurology department due to bradykinesia and rigidity. Even though the patient did not engage in psychiatric treatment, neither affective nor psychotic symptoms were observed. The patient was discharged from the hospital for outpatient follow-up with prescriptions for levodopa and benserazide. At the 6-month follow-up, sertraline at a dose of 50 mg daily was started because of depressive symptoms that were related to PD symptoms and low functionality.
Ochronosis, which is most commonly found in the joints, cardiovascular system, and the liver, has also been detected in the brain of patients with alkaptonuria.3,4 Although renal and cardiovascular manifestations of alkaptonuria are well known, there is a lack of information about neuropsychiatric outcomes in terms of both case reports and mechanism.
In studies conducted thus far, ochronotic pigment deposition and toxicity due to free radicals or electron donor properties of homogentisic acid are suggested to be related to changes in substantia nigra. This phenomenon, named striato-nigral ochronosis, has been demonstrated as the main mechanism in the development of parkinsonian symptoms.9
Alkaptonuria is a genetic disease present at birth, but the obvious symptoms of the disease typically start after age 30 years. The reasons for this delay and the mechanism of natural course are not yet known.16 This patient was diagnosed with alkaptonuria at age 41 years after the development of parkinsonian symptoms.
Although data about psychiatric symptoms associated with alkaptonuria in the literature are lacking, it has been suggested that psychiatric symptoms such as anhedonia and dysthymia can be seen depending on the physiological complications of alkaptonuria in adults.12
In a recent case report, a pediatric patient with alkaptonuria who presented with comorbid attention-deficit/hyperactivity disorder, oppositional defiant/conduct disorder, and borderline intellectual functioning was successfully treated with methylphenidate and risperidone.17
The most common psychiatric conditions observed in PD are depression, anxiety, sleep disorders, sexual dysfunction, cognitive impairment, and psychosis. Mania and impulse control disorders (excessive sexuality, pathological gambling, etc.) may occur in PD, although they are seen less frequently. These psychiatric conditions can occur as a direct result of the disease or due to the dopaminergic agents used for treatment.18 The regression of manic symptoms in our case after the discontinuation of treatment of PD may be related to a reduction in dopaminergic agents. But it is not clear that manic symptoms are a result of treatment (sertraline, levodopa, and carbidopa), PD itself, or totally related to alkaptonuria. The patient's good response to clozapine may be consistent with literature demonstrating that clozapine is effective in PD.19
To our knowledge, this is the first case report of a patient with alkaptonuria with a comorbid diagnosis of PD and affective symptoms. Because the coexistence of psychiatric diseases with neurological and metabolic diseases is a complicating factor for both the diagnosis and the choice of treatment, it can be said that screening for other diseases in patients presenting with psychiatric symptoms is important.
- Millucci L, Spreafico A, Tinti L, et al. Alkaptonuria is a novel human secondary amyloidogenic disease. Biochim Biophys Acta. 2012;1822(11):1682–1691. doi:10.1016/j.bbadis.2012.07.011 [CrossRef] PMID:22850426
- Martin JP Jr, Batkoff B. Homogentisic acid autoxidation and oxygen radical generation: implications for the etiology of alkaptonuric arthritis. Free Radic Biol Med. 1987;3(4):241–250. doi:10.1016/S0891-5849(87)80031-X [CrossRef] PMID:3121448
- Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in ochronosis: review of the literature. Rheumatol Int.2005;25(2):81–85. doi:10.1007/s00296-004-0498-1 [CrossRef] PMID:15322814
- Rovensky J. Manifestations of alkaptonuria and ochronosis in visceral organs. In: Rovensky J, Urbanek T, Boldisova O, eds. Alkaptonuria and Ochronosis. Berlin, Germany: Springer; 2013:73–78.
- Mathieu P, Prevel A, David L, et al. Screening infants for neuroblastoma: discovery of alkaptonuria in one case. Clin Chim Acta.1997;264(2):255–259. doi:10.1016/S0009-8981(97)00097-1 [CrossRef] PMID:9293385
- Abs R, Van Vyve M, Willems PJ, et al. The association of astrocytoma and pituitary adenoma in a patient with alcaptonuria. J Neurol Sci.1992;108(1):32–34. doi:10.1016/0022-510X(92)90184-M [CrossRef] PMID:1624949
- Proctor P. Relationship between alkaptonuria and parkinsonism. Lancet. 1970;2(7680):984. doi:10.1016/S0140-6736(70)92166-5 [CrossRef] PMID:4097631
- Siekert RG, Gibilisco JA. Discoloration of the teeth in alkaptonuria (ochronosis) and parkinsonism. Oral Surg Oral Med Oral Pathol. 1970;29(2):197–199. doi:10.1016/0030-4220(70)90081-2 [CrossRef] PMID:5262835
- Aquaron RR. Alkaptonuria in France: past experience and lessons for the future. J Inherit Metab Dis. 2011;34(6):1115–1126. doi:10.1007/s10545-011-9392-7 [CrossRef] PMID:21927854
- Cox TF, Ranganath L. A quantitative assessment of alkaptonuria: testing the reliability of two disease severity scoring systems. J Inherit Metab Dis. 2011;34(6):1153–1162. doi:10.1007/s10545-011-9367-8 [CrossRef] PMID:21744089
- Sandler M, Karoum F, Ruthven CRJ. Parkinsonism with alkaptonuria: a new syndrome?Lancet. 1970;296(7676):770. doi:10.1016/S0140-6736(70)90240-0 [CrossRef]
- Rana AQ, Saeed U, Abdullah I. Alkaptonuria, more than just a mere disease. J Neurosci Rural Pract.2015;6(2):257–260. doi:10.4103/0976-3147.150312 [CrossRef] PMID:25883496
- Naharci MI, Ak M, Bozoglu E, Karadurmus N, Isik AT, Doruk H. An elderly diabetic case of ochronosis with depression and chronic pain. Endokrynol Pol. 2010;61(6):710–713. PMID:21104647
- Tolosa E, Borght TV, Moreno EDaTSCAN Clinically Uncertain Parkinsonian Syndromes Study Group. Accuracy of DaTSCAN (123I-Ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-year follow-up of an open-label study. Mov Disord. 2007;22(16):2346–2351. doi:10.1002/mds.21710 [CrossRef] PMID:17914722
- de la Fuente-Fernández R. Role of DaTSCAN and clinical diagnosis in Parkinson disease. Neurology. 2012;78(10):696–701. doi:10.1212/WNL.0b013e318248e520 [CrossRef] PMID:22323748
- Ranganath LR, Cox TF. Natural history of alkaptonuria revisited: analyses based on scoring systems. J Inherit Metab Dis. 2011;34(6):1141–1151. doi:10.1007/s10545-011-9374-9 [CrossRef] PMID:21748407
- Arıcı A, Altun H. Successful treatment of attention-deficit/hyperactivity disorder accompanying to alkaptonuria with methylphenidate and risperidone. Psychiatry Clin Psychopharmacol. 2019;29(1):110–113. doi:10.1080/24750573.2018.1432238 [CrossRef]
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