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BRIEF COMMUNICATIONS: C. Fernandez, A. Maues de Paula, D. Figarella-Branger, M. Krahn, R. Giorgi, B. Chabrol, M. -F. Monfort, J. Pouget, and J. -F. Pellissier Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia Neurology 2006; 66: 1585-1587 [Abstract] [Full text] [PDF]

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Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia

Ruth H. Walker, MB, ChB, PhD, Hans H. Jung, Department of Neurology, University Hosp. Zurich, Adrian Danek, MD, Neurologische Klinkink and Polklinik, Ludwig-Maximilians-Univers, Munich, Germany   (12 September 2006)

Reply from the Authors

Carla Fernandez, Dominique Figarella-Branger, André Maues De Paula and Jean-François Pellissier   (12 September 2006)

Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia 12 September 2006
Ruth H. Walker, MB, ChB, PhD, James J. Peters VAMC Department of Neurology (127), 130 W. Kingsbridge Road, Bronx NY 10468, Hans H. Jung, Department of Neurology, University Hosp. Zurich, Adrian Danek, MD, Neurologische Klinkink and Polklinik, Ludwig-Maximilians-Univers, Munich, Germany Send Correspondence to journal: Re: Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia ruth.walker{at}mssm.edu Ruth H. Walker, MB, ChB, PhD, et al.	We read with interest the article on the diagnosis of elevated serum levels of creatine kinase (hyperCKemia) [1], but noted the omission of the diagnosis of the neuroacanthocytosis (NA) syndromes. [2] HyperCKemia is present in the majority of patients with either of the major NA syndromes: autosomal recessive chorea-acanthocytosis (ChAc) or X- linked McLeod syndrome (MLS). [3] In both disorders, there may be EMG and neuropathological evidence of myopathy with atrophy of type 2 fibers. [4] The finding of elevated CK often predates by many years the appearance of neurological features such as frank myopathy, neuropathy, chorea, or seizures. The age of onset of chorea in ChAc ranges from the teens to the seventh decade, appearing in most cases in the 30s. In MLS, the age of onset of chorea ranges from the 20s-60s with most cases presenting from 40-60 years. [3] Cognitive and psychiatric features are also typical and the diagnosis may be obscure until the movement disorder develops. The diagnosis may be masked by the use of neuroleptics, and additionally, the presence of myopathy may predispose to neuroleptic malignant syndrome. [5] Awareness of these disorders as part of the differential diagnosis of hyperCKemia should result in broadening the workup of these findings to include peripheral blood smear for acanthocytes. Elevated liver enzymes are another feature suggestive of these diagnoses. [3] In addition to evaluation for other neurologic features suggestive of NA syndromes (chorea, hyporeflexia, seizures, cognitive impairment, psychopathology), males with unexplained hyperCKemia should be evaluated for possible MLS (determination of the McLeod blood group phenotype in a suitable reference laboratory) and all subjects should be evaluated for ChAc (chorein assay in RBCs). These are available on a research basis at Dr Danek’s laboratory in Munich, Germany. Testing should be preceded by genetic counseling because a positive diagnosis has serious implications for the patient and family. Correct diagnosis of these disorders is essential for prophylactic monitoring for cardiac disease in MLS to avoid further invasive work-up and to provide genetic counseling and prognostic information to patients. References 1. Fernandez C, de Paula AM, Figarella-Branger D et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 2006;66:1585-1587. 2. Danek A, Walker RH. Neuroacanthocytosis. Curr Opin Neurol 2005; 18:386-392. 3. Rampoldi L, Danek A, Monaco AP. Clinical features and molecular bases of neuroacanthocytosis. J Mol Med 2002; 80:475-491. 4. Jung HH, Russo D, Redman C, Brandner S. Kell and XK immunohistochemistry in McLeod myopathy. Muscle Nerve 2001; 24:1346- 1351. 5. Jung HH, Brandner S. Malignant McLeod myopathy. Muscle Nerve 2002; 26:424-427. Disclosure: The authors report no conflicts of interest.
Reply from the Authors 12 September 2006
Carla Fernandez, Laboratoire d'Anatomie Pathologique et Neuropathologie, Hopital de la Timone 264 rue Saint-Pierre, 13385 Marseille, France, Dominique Figarella-Branger, André Maues De Paula and Jean-François Pellissier Send Correspondence to journal: Re: Reply from the Authors carla.fernandez{at}ap-hm.fr Carla Fernandez, et al.	We thank Dr. Walker et al for their interest in our article. [1] The aim of our study was not to provide an exhaustive list of hyperCKemia etiologies but to report our experience concerning the usefulness of muscle biopsy in a context of chronic hyperCkemia with normal clinical examination. Neuro-acanthocytosis syndromes are characterized by choreic movements, dyskinesia and seizures frequently associated with cognitive impairment and psychiatric symptoms in chorea-acanthocytosis and neuromuscular involvement in McLeod syndrome. [2-3] The diagnosis is suggested by the presence of red cell acanthocytosis on blood smear [2-3]. McLeod syndrome is confirmed by serology showing decreased expression of the Kell blood group antigens and the absence of the Kx antigen [2-4]. The genes responsible for chorea-acanthocytosis and McLeod syndrome are respectively the VPS13A and the XK genes. [2-3] Increased CK level is observed in the majority of patients [2,5] and it is likely that the hyperCKemia often precedes the development of the full clinical spectrum of neuro-acanthocytosis. Muscle biopsies of patients suffering from neuro-acanthocytosis generally showed non-specific myopathic changes such as increased variability in fiber size, type grouping, type 1 fiber predominance, type 2 fiber atrophy and centrally located nuclei. [2-6] There is also one report of a patient with inflammatory infiltrates mimicking polymyositis. [7] In one case of McLeod muscle biopsy, immunohistochemistry using antibodies directed against Kell and XK antigens showed a weak and non-specific staining in comparison with control muscle. [4] The authors point out the difficulties of interpretation especially for XK immunohistochemistry [4], making it not easily usable for diagnosis. Few cases of isolated hyperCKemia associated with neuro-acantocytosis have been reported. [6-8] We did not encounter similar cases in our experience but we noticed that chronic hyperCKemia revealing neuro- acanthocytosis is rare but possible. We agree that blood smear and determination of the McLeod blood group phenotype could be part of biological investigations in the case of isolated chronic hyperCKemia. References 6. Witt TN, Danek A, Reiter M, Heim MU, Dirschinger J, Olsen EG. McLeod syndrome: a distinct form of neuroacanthocytosis. Report of two cases and literature review with emphasis on neuromuscular manifestations. Neurol;239:302-306. 7. Barnett MH, Yang F, Iland H, Pollard JD. Unusual muscle pathology in McLeod syndrome J Neurol Neurosurg Psychiatry 2000;69:655-657. 8. Lossos A, Dobson-Stone C, Monaco AP et al. Early clinical heterogeneity in choreoacanthocytosis. Arch Neurol. 2005;62:611-614. Disclosure: The authors report no conflicts of interest.