Movement disorders in adult surviving patients with maple syrup urine disease Movement Disorders in Adult Surviving Patients with Maple Syrup Urine Disease Miryam Carecchio, MD,1,2 Susanne A. Schneider, MD, PhD,1,3 Heidi Chan, BSc,4 Robin Lachmann, MRCP, PhD,4 Philip J. Lee, MD, FRCP,4 Elaine Murphy, MRCP, FRCPath,4 and Kailash P. Bhatia, MD, FRCP1* 1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, London, United Kingdom 2Department of Neurology, Amedeo Avogadro University, Novara, Italy 3 Schilling Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Luebeck, Luebeck, Germany 4 Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom ABSTRACT: Maple syrup urine disease is a rare metabolic disorder caused by mutations in the branched- chain a-keto acid dehydrogenase complex gene. Patients generally present early in life with a toxic encephalopathy because of the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and the corre- sponding ketoacids. Movement disorders in maple syrup urine disease have typically been described during decompensation episodes or at presentation in the con- text of a toxic encephalopathy, with complete resolution after appropriate dietary treatment. Movement disorders in patients surviving childhood are not well documented. We assessed 17 adult patients with maple syrup urine disease (mean age, 27.5 years) with a special focus on movement disorders. Twelve (70.6%) had a movement disorder on clinical examination, mainly tremor and dys- tonia or a combination of both. Parkinsonism and simple motor tics were also observed. Pyramidal signs were present in 11 patients (64.7%), and a spastic-dystonic gait was observed in 6 patients (35.2%). In summary, movement disorders are common in treated adult patients with maple syrup urine disease, and careful neu- rological examination is advisable to identify those who may benefit from specific therapy. VC 2011 Movement Dis- order Society Key Words: maple syrup urine disease; metabolic; movement disorders; dystonia; parkinsonism Maple syrup urine disease (MSUD, OMIM #248600) is a rare inborn error of metabolism caused by a deficiency in the activity of the branched-chain a- keto acid dehydrogenase (BCKD) complex. As a con- sequence, the degradation of the 3 branched-chain amino acids (BCAAs) leucine, isoleucine, and valine is blocked after the first catabolic step (transamination), resulting in accumulation of BCAAs and the corre- sponding branched-chain a-keto acids (BCKAs) in bio- logical fluids. MSUD is inherited as an autosomal recessive disor- der, and its worldwide frequency is estimated as 1:185,000,1 although in the Mennonite population of Lancaster and Lebanon counties in Pennsylvania its frequency is higher, with a prevalence of approxi- mately 1 in 176 newborns.2 The human BCKD complex is a multienzymatic macromolecule composed of 3 catalytic subunits (E1, with an a2b2 structure, E2, and E3) encoded by differ- ent genes located on chromosomes 19, 6, 1, and 7, respectively. Mutations in each of these loci are re- sponsible for different molecular phenotypes indicated as type IA (E1a), type IB (E1b), type II (E2), and type III (E3).1 Depending on the clinical presentation and the residual enzymatic activity of BCKD, 5 phenotypes are recognized: classic, intermediate, intermittent, thia- mine responsive, and E3 deficient.1,3 Classic MSUD is the most common form, and affected newborns ------------------------------------------------------------ Additional Supporting Information may be found in the online version of this article. *Correspondence to: Prof. Kailash P. Bhatia, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, London, United Kingdom; k.bhatia@ion.ucl.ac.uk Funding agencies: This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres’ funding scheme. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 21 October 2010; Revised: 6 December 2010; Accepted: 10 December 2010 Published online 11 April 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.23629 R E S E A R C H A R T I C L E 1324 Movement Disorders, Vol. 26, No. 7, 2011 present with lethargy, poor sucking, and rapidly pro- gressive encephalopathy in the first days of life, when the characteristic odor of burnt sugar may be noted. Alterations of muscular tone and abnormal dystonic extensions of the arms can occur during this stage of disease.4 Increased blood, urine, and cerebrospinal fluid BCAAs (especially leucine) are found during acute metabolic decompensation, often provoked by intercurrent illness, fasting, injury, or surgery and con- tributed to by endogenous protein catabolism. Patients with MSUD later on may develop neurolog- ical sequelae such as spasticity and quadriplegia as a consequence of the damage resulting from widespread cerebral edema at first clinical presentation or during decompensation episodes.5 Movement disorders can be part of the manifesta- tions of various metabolic diseases,6 alone or in com- bination with other neurological findings. An increasing number of individuals with MSUD are sur- viving childhood thanks to a BCAA-restricted diet, but little information on the prevalence of movement dis- orders in these adults is available. We present the clin- ical neurological findings of 17 adult patients with MSUD, with a particular emphasis on the spectrum of movement disorders. Patients and Methods Seventeen patients (11 women, 6 men; mean age, 27.5 years) diagnosed with MSUD followed up at the Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, were reviewed. This is a tertiary adult referral centre with close links to the pediatric service where patients with MSUD are followed up until age 16 after initial diagnosis. Relevant details about patients’ medical history were obtained from their files and by direct questioning of ei- ther the patients themselves or their caregivers. All patients underwent a full neurological examination by a single neurologist, along with metabolic follow-up including determination of plasma BCAAs. Thirteen patients were diagnosed with classic, 2 with intermittent, and 2 with intermediate MSUD. Disease duration at the time of examination ranged from 17 to 48 years (mean, 27 years), and all but 2 classic cases were diagnosed within the first 3 weeks of life. The 4 nonclassic cases were diagnosed between 2 and 4 years of age. In all patients, the diagnosis of MSUD was based on clinical suspicion and confirmed by measuring elevated BCAA levels in blood and urine. Genetic anal- ysis was not routinely included in the diagnostic workup. One Ashkenazi Jewish patient was tested on a research basis and was found to carry a previously described homozygous mutation (c.548G>C, p.Arg183Pro) in exon 5 of the BCKDHB gene, encod- ing the E2-b subunit of the BCKD complex. Patients with classic MSUD were all on a protein-re- stricted diet (mean protein intake, 9.8 g/day) and amino acid supplementation, whereas 3 of the 4 nonclassic cases were on an unrestricted diet, and 1 followed a vegetarian diet. Demographic data of the patients are shown in Table 1. Results Twelve of 17 patients (70.6%) had a movement dis- order detectable on clinical examination. Tremor was TABLE 1. Demographic features of MSUD patients Patient number Sex Age Movement disorder Disease duration (y) Diet Daily protein intake (g) 1 F 23 Y 23 Y 5 2 M 27 Y 27 Y 5.5 3 M 18 N 18 Y 8 4 F 31 N 31 Y 8 5 F 17 Y 17 Y 8 6 F 25 Y 25 Y 8 7 F 33 Y 33 Y 10 8 F 27 N 27 Y 10 9 M 20 Y 20 Y 11 10 F 31 Y 31 Y 12 11 M 33 Y 33 Y 12 12 F 48 Y 48 Y 18 13 M 26 Y 26 Y 12 14a F 30 N 28 N Unrestricted 15a M 25 Y 23 N Unrestricted 16a F 25 Y 25 N Unrestricted 17a F 29 N 25 N Vegetarian Total 11 F 6 M 27.5 (mean) 12 Y 5 N 27 (mean) 11 Y 6 N 9.8 (mean) aNonclassic MSUD patients. M O V E M E N T D I S O R D E R S I N A D U L T M S U D P A T I E N T S Movement Disorders, Vol. 26, No. 7, 2011 1325 present in 7 subjects (41.1%), alone (1 case) or in combination with other movement disorders: dystonia in 6 (35.3%), parkinsonism in 3 (17.6%; see Video Segment 3), and simple motor tics in 1 (5.9%). Among the patients with a movement disorder (n ¼ 11), tremor and dystonia were the most common find- ings on examination, being detected in 63.6% and 54.5% of subjects, respectively. Of these, 3 patients (27.2%) exhibited a tremor at rest (asymmetric in 2 cases, symmetric in 1 case), 5 patients (45.5%) a pos- tural tremor, and 2 patients (18%) an intention tremor. Among patients with dystonia, 5 (45.5%) had a dystonic posture affecting the hands and 3 (27.2%) the feet, presenting as bilateral plantar flexion and inversion in 1 case and as part of a scissoring-dystonic gait in 2 cases (see Video Segments 1 and 2), and 2 cases (18%) displayed cervical dystonia. Four of 5 patients with dystonia also had a tremor in the affected part of the body, suggesting a dystonic tremor. All patients with parkinsonism presented bra- dykinesia on finger tapping (symmetric in 1 patient, asymmetric in 2 patients) with no rest tremor. One patient showed additional features including facial hypomimia and poverty of movements, loss of pos- tural reflexes, and bilateral reduction of arm swings, along with cogwheel rigidity in the left upper limb. In 1 case simple motor tics were detected on exami- nation, manifesting as brief neck rotations to the left, which were partially suppressible with distraction, but we cannot exclude that this finding was incidental. In all patients the distribution of movement disorders was in the upper part of the body, with additional involvement of the lower limbs in 3 cases. Table 2 summarizes the movement disorders found in the patients examined. In addition to movement disorders, pyramidal signs such as brisk reflexes and spasticity were frequent on examination, overall being present in 11 patients (64.3%). Six showed a scissoring-dystonic gait and were significantly disabled. Language impairment was present in 6 of 17 patients (35.2%), including spastic dysarthria in 4 and slurred speech in 2. Four patients (23.5%) had epilepsy that required pharmacological treatment. Neuropsychiatric disturbances including depression and obsessive-compulsive disorder were present in 2 subjects (11.7%), whereas various degrees of learning difficulties with mental retardation were shown in 10 of 17 cases (58.8%). Discussion In this observational study, we describe the spectrum of movement disorders in adults with MSUD. MSUD is a rare metabolic disorder that generally presents with a toxic encephalopathy within the first days of life. Long- term outcomes in treated adult patients have been diffi- cult to establish because of the rarity of the disorder and its severity on initial presentation, often leading to premature death. It is well recognized that various movement disorders can be present in metabolic condi- tions, often being secondary to early cerebral damage,3 but the spectrum of movement disorders in MSUD is unknown. Although we have previously described neu- ropsychometric outcomes in some patients included in this study,7 no detailed studies have been published on long-term motor signs. In our series of 17 patients, more than two thirds exhibited a movement disorder on clinical examina- tion, mainly tremor and dystonia or a combination of both. These were present in the upper limbs in all cases, with additional involvement of the neck in 2 patients and of the lower limbs in 3 patients. Aside from movement disorders, the most common neuro- logical findings were pyramidal signs in the lower limbs and learning difficulties, observed in 64.7% and 58.8% of cases, respectively. The combination of dys- tonia and spasticity in the lower limbs was the most disabling clinical finding, significantly reducing patients’ ability to walk independently and thus inter- fering with their quality of life. To date, movement disorders in MSUD have only been described as part of the symptoms at onset in the context of a toxic encephalopathy, as recurrent parox- ysmal ataxia or paroxysmal dystonia in intermittent variant MSUD, and during episodes of decompensa- tion.1,8,9 In these cases, movement disorders tended to resolve after appropriate dietary treatment. In our series of adult patients, many had a persistent movement disorder, even when on a strict dietary regi- men in the absence of intercurrent metabolic decom- pensation. Interestingly, we did not observe major cerebellar signs such as ataxia, as previously reported,3 at presentation or during decompensation episodes TABLE 2. Neurological findings in adult patients with MSUD Clinical finding Type Number (percentage) Movement disorders (12 of 17 patients) Tremor 7 (41.1%) —At rest 3 —Postural 5 —Intention 2 Dystonia 6 (35.3%) —Cervical 2 —Upper limbs 5 —Lower limbs 3 Parkinsonism 3 (17.6%) Other movement disorders 1 (5.9%) Other neurological findings (11 of 17 patients) Pyramidal signs 11 (64.7%) Scissoring-dystonic gait 6 (35.2%) Language impairment 6 (35.2%) Neuropsychiatric disturbances 2 (11.7%) Cognitive impairment 10 (58.8%) Epilepsy 4 (23.5%) C A R E C C H I O E T A L . 1326 Movement Disorders, Vol. 26, No. 7, 2011 consistent with a typical severe cerebellar edema seen on neuroimgaing10 and with prominent neuropatho- logical alterations in the cerebellum.1 There is considerable interest in movement disorders due to metabolic diseases, as this can provide some answers with regard to pathophysiology, as recently exemplified by Gaucher’s disease–related parkinson- ism. Our clinical observations raise the question of the nature of the underlying pathophysiology of move- ment disorders seen in adult MSUD patients. With regard to the neuropathology, it is known that in MSUD considerable neuronal loss is present in the pontine nuclei and substantia nigra,11 and striatal damage has been demonstrated both in the animal model of MSUD12 and in affected children.4 Moreover, leucine has a high affinity for the L1-neu- tral amino acid transporter through which other amino acids are transported into the central nervous system; therefore, high leucine plasma concentrations reduce the uptake of some amino acids in the brain, including phenylalanine, tyrosine, and tryptophan. This leads to the depletion of some neurotransmitters in the brain such as dopamine and serotonin, as dem- onstrated in the animal model of MSUD by Zinnanti et al,13 who observed a reduction in dopamine levels in the brain of MSUD mice by more than 60% along with decreased GABA and glutamate levels. The depletion of neurotransmitters, especially dopamine, was concomitant with the initiation of limb dystonia and gait abnormalities in MSUD mice. Although these findings were described during acute encephalopathy, it is possible that altered neurotrans- mitter levels, especially dopamine, are present as a long- term consequence in the brains of adult MSUD patients, being responsible for the development of dystonia, as seen in other diseases characterized by reduced dopa- mine availability (juvenile Parkinson’s disease, dopa-re- sponsive dystonia).14,15 Interestingly, in a series of 36 infants, dystonia was observed at onset in 42.2% of patients, being associated with high serum leucine-to- tyrosine ratios and thus further suggesting that acute leucinosis with secondary tyrosine deficiency may con- tribute to the development of dystonia.4 Finally, the development of movement disorders in MSUD mice has been further explained by a disrup- tion of the cerebral energy metabolism from the toxic effect of BCKA in the central nervous system with reduced ATP and phosphocreatine levels,13 which may affect the normal functioning of basal ganglia and other parts of the brain highly dependent on the mito- chondrial respiratory chain. In addition to these neurochemical changes that may at least be partly responsible for the movement disor- ders observed in our patients, the permanent damage resulting from early encephalopathy at onset is likely to play a role in the development of movement disor- ders. In this regard, 3 of our patients with a move- ment disorder (parkinsonism; rest tremor; dystonia and spastic-dystonic gait) underwent a brain MRI scan that did not show any abnormality of either the basal ganglia or the cerebellum. However, we cannot exclude that other patients included in our series might have a structural damage on neuroimaging. It may be that given the above-mentioned biochemi- cal alterations, the development of movement disor- ders in MSUD is associated with the number as well as the severity of decompensation episodes. However, in our series it was not possible to clearly define the total number of decompensation episodes throughout life, as not all resulted in hospital admission or were clearly documented. With regard to the treatment of movement disorders, symptomatic drugs such as local botulinum toxin injec- tions in patients with dystonia or dopaminergic drugs in those with parkinsonism should be considered as poten- tial treatments in the future. No cases of deep brain stimulation (DBS) in patients with MSUD and move- ment disorder have been reported so far, but DBS has been successfully used in a few cases of other inborn errors of metabolism also presenting with movement disorders such as Lesh-Nyhan syndrome.16,17 Conclusions Movement disorders have been described in MSUD at onset or during decompensation episodes, mainly as paroxysmal dystonia or ataxia. In this study, we assessed 17 adult patients with MSUD and observed a high prevalence of movement disorders, even in patients with a long disease duration following a pro- tein-restricted diet and under relatively stable meta- bolic control. Dystonia in the upper limbs and tremor were the most frequent findings. We speculate that these symptoms may be secondary to cerebral damage from toxic encephalopathy at onset and during recur- rent acute decompensation and/or chronic reduced lev- els of neurotransmitters, such as dopamine, as demonstrated in the animal model of MSUD. Our findings suggest that a careful neurological assessment is advisable in adult patients with MSUD, and we recommend screening these patients for move- ment disorders such as dystonia and parkinsonism, as these symptoms are potentially treatable. Further stud- ies are needed to clarify the pathophysiology of move- ment disorders in MSUD in order to offer patients specific treatments to improve their quality of life. Legends to the Video Video Segment 1. Seventeen-year-old patient. Dys- tonic posture of feet (inversion) with gait showing M O V E M E N T D I S O R D E R S I N A D U L T M S U D P A T I E N T S Movement Disorders, Vol. 26, No. 7, 2011 1327 mixed dystonia and spasticity. Cervical dystonia (left torticollis, mild retrocollis, and left shoulder eleva- tion). Mild dystonic posture of the right hand, with slowness in performing finger tapping bilaterally with- out evidence of clear decrement. Video Segment 2. Thirty-one-year-old patient. Dys- tonic posture of feet and toes and a gait with a mixture of dystonia and spasticity. A bilateral dystonic posture of both hands, more marked on the right side, is visible on walking and keeping arms outstretched. Mild cervi- cal dystonia (right torticollis) is also detectable. 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