Response of Motor Complications in Cockayne Syndrome to Carbidopa-Levodopa

Home , Cockayne syndrome, Trichothiodystrophy

OBSERVATION Response of Motor Complications in Cockayne Syndrome to Carbidopa-Levodopa

Edward G. Neilan, MD, PhD; Mauricio R. Delgado, MD; Melissa A. Donovan, BA; Sara Y. Kim, BS; Rita L. Jou, SB; Bai-Lin Wu, PhD, MMed; Peter B. Kang, MD

Background: Gait difficulties, tremors, and coordina- Intervention: Carbidopa-levodopa therapy. tiondifficultiesarecommonfeaturesofCockaynesyndrome that are consequences of leukodystrophy, cerebellar at- Main Outcome Measures: Status of tremors, ability rophy, and demyelinating neuropathy, but no pharmaco- to perform daily tasks, serial physical examinations, and therapy for these disabling symptoms is available. results of handwriting samples.

Objective: To determine whether carbidopa-levodopa Results: All 3 patients had a clear reduction in tremors relieves tremors and other motor complications of Cock- and improvements in handwriting and manipulation of ayne syndrome. utensils and cups.

Design: Mutation analysis and case report study. Conclusions: Patients with Cockayne syndrome should be evaluated carefully for movement disorders. A clini- Setting: Hospital clinic and genetics research laboratory. cal trial should be considered to evaluate this therapy further. Patients: We studied 3 patients with Cockayne syndrome, a rare autosomal recessive neurodegenerative disorder for which no known treatments are available. Arch Neurol. 2008;65(8):1117-1121

OCKAYNE SYNDROME (CS) netic study of CS, we studied 3 adoles- is a rare autosomal reces- cents with a relatively mild course who had sive neurodegenerative clear tremors and motor difficulties. disorder caused by mutations in ERCC8 (CSA or METHODS CKN1C)1 and ERCC6 (CSB).2 The clinical phenotype of CS is distinctive and in- cludes microcephaly, intellectual disabil- The setting was a hospital clinic and genetics research laboratory. Patients and their parents were ity, short stature, cutaneous photosensi- enrolled in a research study of the genetics of CS tivity, pigmentary retinopathy, cachexia, following an approved protocol of the Chil- 3,4 premature aging, and deafness. dren’s Hospital Boston, and informed written The pathophysiologic features involve a consent was obtained. Mutation analysis of the defect in nucleotide excision repair (NER), ERCC8 (CSA) and ERCC6 (CSB) genes was per- a process that reverses a range of DNA helix- formed by direct DNA sequencing of the cod- distorting lesions, including damage caused ing exons and their flanking splice junctions on by UV radiation.5 Cockayne syndrome is a DNA analyzer (ABI Prism DNA Analyzer; Ap- classified as an NER disorder, along with xe- plied Biosystems, Foster City, California). Con- roderma pigmentosum, which is character- trol DNA samples were obtained anonymously Author Affiliations: Division of from 96 patients unaffected by CS. Three pa- Genetics (Dr Neilan and ized by severe cutaneous photosensitivity tients with CS identified through this genetic Mss Donovan, Kim, and Jou) and a high risk of skin cancer, and tricho- study were given therapeutic trials of carbidopa- and Departments of Laboratory thiodystrophy, which is associated with pho- levodopa on a clinical basis. Medicine (Dr Wu) and tosensitivity, poor growth, neurodegenera- Neurology (Dr Kang), tion, and brittle hair.6 Children’s Hospital Boston and Gait difficulties, tremors, and coordi- RESULTS Harvard Medical School, nation difficulties are common features of Boston, Massachusetts; and PATIENT 1 Department of Neurology, Texas CS that are consequences of leukodystro- Scottish Rite Hospital for phy, cerebellar atrophy, and demyelinat- Children and University of ing neuropathy, but no pharmaco- A 13-year-old, right-handed girl with CS Texas Southwestern Medical therapy for these disabling symptoms is had increased muscle tone in the lower ex- Center, Dallas (Dr Delgado). available. Among patients enrolled in a ge- tremities (left greater than right) since the

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 8), AUG 2008 WWW.ARCHNEUROL.COM 1117

Patient No.a

Clinical Features 123 Gestation, wk 36 39 28-32 Began walking, mo 15 17-18 13 Began speaking, mo 18 16 Normal Height, cm (percentile) 134.2 (Ͻ3rd) 129.0 (Ͻ3rd) 131.0 (Ͻ3rd) Weight, kg (percentile) 38.1 (10th-25th) 22.3 (Ͻ3rd) 29.0 (Ͻ3rd) Head circumference, cm (percentile) 49 (Ͻ3rd) 50 (Ͻ3rd) 43 (Ͻ3rd) Neuroimaging findings Basal ganglia mineralization and Basal ganglia and pineal gland Small caudate nuclei, prominent abnormal periventricular and calcifications, cerebral and cerebellar cerebral ventricles, and thin subcortical myelination atrophy, and delayed myelination corpus callosum

a All 3 patients had the following clinical features: deep-set eyes, pigmentary retinopathy (mild in patient 3), and sensorineural hearing loss.

present, with dysmetria and dysdiadochokinesia, but she A had neither a postural or resting tremor. She navigated CSA 37G > T (E13X) stairs with mild difficulty and some bradykinesia. Fur- ther clinical details are given in Table 1. Motor nerve conduction studies of the right tibial nerve recording ab- A C G G G T T T G G A G G A C C C T C T ductor hallucis brevis demonstrated slowing of nerve con- B duction, with a latency of 6.7 milliseconds (reference CSA IVS11-1G > C range, Ͻ5.7 milliseconds), an amplitude of 5.9 mV with ankle stimulation and 3.1 mV with popliteal stimulation (reference range, Ͼ2.8 mV), and a velocity of 26 m/s T T T T T T T T T A G A C T A C A A C A (reference range, Ͼ41 m/s). F-response latency was 40 C Ͻ C milliseconds (reference range, 56 milliseconds). Bilat- CSA 479C > T (A160V) eral sural sensory responses were absent. Mutation analysis demonstrated inheritance of 2 compound heterozygous CSA mutations by this patient: G T T T G G T A G C A G G T T T G T A c.37GϾT (p.E13X), a nonsense mutation inherited from T D the father that was previously reported in an unrelated 7 Ͼ CSA 1052G > A (S351N) patient with CS ; and IVS11-1G C, a novel splice ac- ceptor mutation inherited from the mother that alters the invariant AG dinucleotide (Figure 1A and B). Neither

A A C T T T A T A G T G G T A G C A G mutation was present in the control samples. The re- A sults of genetic testing for GCH1 were negative, exclud- E ing the classic form of dopa-responsive dystonia. CSB 3806A > C (D1269A) A combination of carbidopa, 25 mg, and levodopa, 100 mg, was prescribed at initially a half tablet by mouth twice a day and then increased to 1 tablet twice a day. Approxi- T G A A G C A C G A T G C C A T C A T C mately 1 week after starting the full dose, she and her parents noticed a reduction in her tremors, improve- Figure 1. DNA sequence chromatograms: CSA gene sequencing ment in her handwriting, and better manipulation of uten- demonstrates compound heterozygous mutations in patients 1 (A and B) and sils. Eight weeks after the initial visit, her handwriting 2 (C and D); CSB gene sequencing demonstrates a heterozygous mutation in sample showed marked improvement (Figure 2A and patient 3 (E). Arrowheads indicate locations of the mutations. B), her hypertonia had improved, and her dysmetria had diminished, with a significant beneficial effect on her age of 15 months. Her parents first observed bilateral hand schoolwork. tremors at 3 or 4 years of age. She has an unsteady gait and difficulty with motor tasks, including writing, hold- PATIENT 2 ing beverages, buttoning, zipping, and putting on socks and shoes. She uses training wheels on her bicycle. A 14-year-old boy with CS had significant tremors that Physical examination findings revealed bilateral heel limited his activities of daily living. He had poor feeding cord contractures, jerky ocular pursuits, and dysmetric through the first year of life. Acquired microcephaly was saccades. Fluctuating dystonia was present in both legs, observed at the age of 14 months. He was diagnosed clini- with mild distal weakness. Tendon stretch reflexes were cally as having CS at the age of 5 years. He began riding diminished in the arms and at the patellae and absent at a bicycle at 5 years. Chronic complications of CS ob- the ankles, with flexor plantar responses. Vibration sen- served include tremors, hypertonia, decreased lacrima- sation was diminished. Bilateral intention tremors were tion, and cutaneous photosensitivity.

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 8), AUG 2008 WWW.ARCHNEUROL.COM 1118

©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Physical examination findings revealed hypertonia and hyperreflexia, head titubations, severe resting and inten- A B tion tremors, dysmetria, dysdiadochokinesia, and a wide- based ataxic gait. Further clinical details are given in Table 1. Neuroimages are presented in Figure 3. Mutation analysis demonstrated 2 compound heterozygous CSA point mutations: c.479CϾT (p.A160V), a missense mutation inherited from the mother that was previously reported in another patient8; and c.1052GϾA (p.S351N), a novel missense mutation inherited from the father (Figure 1C and D). Neither mutation was found in the control samples. His tremors caused significant difficulty writing, feeding, and dressing. A trial of clonazepam did not result in an improvement in the tremors. He was prescribed a combination of carbidopa, 25 mg, and levodopa, 100 mg, and took half a tablet each morning, which improved his trem- C D ors; the resting tremor improved more than the intention tremor. The dose was gradually increased, and after 8 months he was taking 1 full tablet twice a day. His handwriting has improved, and he can color much more accu- rately than before. He has better endurance with activities such as walking, swimming, and riding a bicycle.

PATIENT 3

A 14-year-old girl with developmental delays was at her baseline until 2 years before presentation, when she developed motor difficulties. She was no longer able to climb a rope ladder or ride a pony. She developed gait difficulties, falls, tremors, choking and gagging on food, difficulty buttoning and zipping clothes, difficulty tying shoe- laces, and problems navigating stairs. Her birth history was notable for the ultrasonographic finding of dilated cere- Figure 2. Handwriting samples from the study patients: sample from patient bral ventricles and tube feedings in the first week of life. 1 when not receiving (A) and receiving (B) carbidopa-levodopa; and sample Physical examination findings revealed a beaked nose from patient 3 when not receiving (C) and receiving (D) carbidopa-levodopa. Note the large, irregularly formed letters when the patient was not taking and bilateral hand weakness. Tendon stretch reflexes were medication (A and C) and the smaller, firmer writing, with straighter lines normal in the upper extremities, increased at the patellae, and rounder curves, when the patient was taking medication (B and D). Each 1 ϫ and absent at the ankles, with extensor plantar responses. panel was scanned from an 8 ⁄2 11-in sheet of paper. She had fluctuating rigidity in the upper extremities, es- pecially at the elbows, but without contractures. Dysmet- improved, and her steps were less shuffling. At 6 months, ria and dysdiadochokinesia were present. She had a mild she continued to have clear improvements in multiple mo- coarse postural tremor bilaterally and a shuffling gait with tor tasks with a significant beneficial effect on her daily life. bradykinesia. Further details are given in Table 1. Nerve At the 6-month visit, thyroid studies demonstrated mild conduction studies demonstrated a mild sensory polyneu- hypothyroidism and thyroid supplementation was initi- ropathy (Table 2), and the results of needle electromy- ated. Nerve conduction studies demonstrated a sensory neu- ography of the right leg were normal. ropathy, possibly related to the thyroiditis. Vitamin B and Mutation analysis demonstrated 1 novel heterozy- 12 vitamin E levels were normal. Cerebrospinal fluid neuro- gous missense mutation in CSB, c.3806AϾC (p.D1269A), transmitter metabolite, 5-methyltetrahydrofolate, neop- which was inherited from the asymptomatic father terin, and biopterin levels were essentially normal during but was not observed in any of the control samples a break from taking carbidopa-levodopa. Handwriting (Figure 1E). As yet, no other mutation in CSB has been samples taken during and after this drug break illustrate identified in this patient. No mutations in CSA have been the effect (Figure 2C and D). identified, but CSB protein was deficient in cultured skin fibroblasts (E.G.N., unpublished data, October 27, 2006). The results of genetic testing for GCH1 mutations were COMMENT negative. Therapy with a combination of carbidopa, 25 mg, and We describe 3 adolescents with CS, all of whom had trem- levodopa, 100 mg, was initiated at a half tablet twice a day. ors and motor difficulties that responded to therapy with Three months later, her tremor had resolved, she used uten- carbidopa-levodopa, with a significant beneficial effect sils more adroitly, she dressed herself better than before, on their daily activities and ability to care for them- and her movements were smoother. Her hypertonia had selves. These activities included tasks such as writing,

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 8), AUG 2008 WWW.ARCHNEUROL.COM 1119

Figure 3. Cranial computed tomographic scans, taken at the ages of 9 years (A) and 15 years (B); the scans demonstrate bilateral basal ganglia mineralization and diffuse brain atrophy. The basal ganglia mineralization remains stable during this interval, whereas the ex vacuo ventricular dilation becomes more prominent over time.

Table 2. Nerve Conduction Data for Patient 3

Nerve Latency, msa Amplitudeb Velocity, m/s Right median sensory 2.80 31.90 54.80 Right superficial peroneal sensory 2.85 5.20 43.90 Right sural sensory No response No response No response Left sural sensory No response No response No response Right common peroneal motor Ankle 4.70 3.50 Not applicable Fibular head 11.35 3.00 42.10 Popliteal fossa 13.25 3.00 42.10 Right tibial motor Ankle 3.25 9.10 Not applicable Popliteal fossa 10.30 6.10 46.10

a Latency is peak for the sensory studies and onset for the motor studies. b Amplitude is given in microvolts for the sensory studies and in millivolts for the motor studies.

dressing, and eating and drinking. The parents of all 3 tures of CS with those of Parkinson disease. In Parkin- patients reported worsening of tremors and increased dif- son disease, degeneration of the substantia nigra oc- ficulty with motor tasks when doses of carbidopa- curs, which provides dopaminergic input to the putamen. levodopa were unintentionally missed. This simple in- Calcification of the putamen is a hallmark of CS,10 with tervention has the potential to improve the quality of life lesser degrees of calcification in the caudate, globus pal- significantly in affected individuals. lidus, and thalamus.11 In addition, the expression of glu- Our findings raise intriguing questions regarding the tamate transporters appears to be altered in the globus pathogenesis and therapy of CS. Delayed-onset progres- pallidus.12 Neuropathologic studies generally suggest pres- sive movement disorders have been observed in the set- ervation of the substantia nigra; however, 1 report13 ob- ting of static acquired brain lesions, such as perinatal in- served brown discoloration of the substantia nigra. These jury, stroke, and head trauma.9 Further localization is findings suggest that the dopaminergic pathway may be suggested by a comparison of the neuropathologic fea- injured in CS. There is also 1 report14 of a patient with

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 8), AUG 2008 WWW.ARCHNEUROL.COM 1120

©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 CS whose hyperkinetic movement disorder improved with Parzych, BA, and Ashley Catalano, BS, assisted with the deep brain stimulation of the ventral intermediate nucleus figures, and Amy R. Danehy, MD, interpreted the neu- of the thalamus. Some of our patients’ physical findings roimaging studies. suggest the presence of cerebellar dysfunction, but the significance of this is unclear in light of the pathologic findings and their response to levodopa-carbidopa. REFERENCES The link between the pathologic findings in the basal ganglia and the NER pathway is not yet clear. Recent 15 1. Henning KA, Li L, Iyer N, et al. The Cockayne syndrome group A gene encodes a work suggests that endogenous DNA damage may con- WD repeat protein that interacts with CSB protein and a subunit of RNA poly- tribute to the pathophysiologic features of NER disor- merase II TFIIH. Cell. 1995;82(4):555-564. ders. It is possible that the deep nuclei of the basal gan- 2. Troelstra C, van Gool A, de Wit J, Vermeulen W, Bootsma D, Hoeijmakers JH. glia are more vulnerable to endogenous DNA damage and ERCC6, a member of a subfamily of putative helicases, is involved in Cock- ayne’s syndrome and preferential repair of active genes. Cell. 1992;71(6):939- preferentially degenerate in CS, thus causing the move- 953. ment disorders observed in our patients. Because this in- 3. Pasquier L, Laugel V, Lazaro L, et al. Wide clinical variability among 13 new Cock- tervention in CS has not previously been described, fur- ayne syndrome cases confirmed by biochemical assays. Arch Dis Child. 2006; ther studies are warranted. 91(2):178-182. 4. Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet. 1992;42(1):68-84. Accepted for Publication: January 4, 2008. 5. Andrews AD, Barrett SF, Robbins JH. Xeroderma pigmentosum neurological ab- Correspondence: Peter B. Kang, MD, Department of Neu- normalities correlate with colony-forming ability after ultraviolet radiation. Proc rology, Fegan 11, Children’s Hospital Boston, 300 Long- Natl Acad Sci U S A. 1978;75(4):1984-1988. wood Ave, Boston, MA 02115 (peter.kang@childrens 6. Kraemer KH, Patronas NJ, Schiffmann R, Brooks BP, Tamura D, Digiovanna JJ. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a com- .harvard.edu). plex genotype-phenotype relationship. Neuroscience. 2007;145(4):1388-1396. Author Contributions: Study concept and design: Neilan, 7. Cao H, Williams C, Carter M, Hegele RA. CKN1 (MIM 216400): mutations in Cock- Wu, and Kang. Acquisition of data: Neilan, Delgado, ayne syndrome type A and a new common polymorphism. J Hum Genet. 2004; Donovan, Kim, Jou, Wu, and Kang. Analysis and inter- 49(1):61-63. pretation of data: Neilan, Delgado, Jou, Wu, and Kang. 8. Ridley AJ, Colley J, Wynford-Thomas D, Jones CJ. Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C Drafting of the manuscript: Kang. Critical revision of the subjects. J Hum Genet. 2005;50(3):151-154. manuscript for important intellectual content: Neilan, 9. Scott BL, Jankovic J. Delayed-onset progressive movement disorders after static Delgado, Donovan, Kim, Jou, Wu, and Kang. Obtained brain lesions. Neurology. 1996;46(1):68-74. funding: Neilan. Administrative, technical, and material sup- 10. Itoh M, Hayashi M, Shioda K, et al. Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev. 1999;21(5):326-333. port: Neilan, Jou, and Wu. Study supervision: Kang. 11. Soffer D, Grotsky HW, Rapin I, Suzuki K. Cockayne syndrome: unusual neuro- Financial Disclosure: None reported. pathological findings and review of the literature. Ann Neurol. 1979;6(4):340- Funding/Support: This study was supported by the Na- 348. tional Organization for Rare Disorders, Mark and 12. Hayashi M, Itoh M, Araki S, et al. Oxidative stress and disturbed glutamate trans- Katherine Pelson, the Luke O’Brien Foundation, and the port in hereditary nucleotide repair disorders. J Neuropathol Exp Neurol. 2001; 60(4):350-356. Ben & Riley Sullivan Golf Outing (Dr Neilan); and by 13. Rapin I, Weidenheim K, Lindenbaum Y, et al. Cockayne syndrome in adults: re- grant K08 NS48180 from the National Institute of Neu- view with clinical and pathologic study of a new case. J Child Neurol. 2006; rological Disorders and Stroke (Dr Kang). 21(11):991-1006. Additional Contributions: We thank the families for par- 14. Hebb MO, Gaudet P, Mendez I. Deep brain stimulation to treat hyperkinetic symptoms of Cockayne syndrome. Mov Disord. 2006;21(1):112-115. ticipating in this project and providing the handwriting 15. Brooks PJ. The case for 8,5Ј-cyclopurine-2’-deoxynucleosides as endogenous samples. Joseph J. Volpe, MD, and Basil T. Darras, MD, DNA lesions that cause neurodegeneration in xeroderma pigmentosum. provided helpful comments on the manuscript, Julia Neuroscience. 2007;145(4):1407-1417.

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 8), AUG 2008 WWW.ARCHNEUROL.COM 1121