Spasmodic Muscle Cramps and Weakness as Presenting Symptoms in Wilson Disease

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Spasmodic Muscle Cramps and Weakness as

Presenting Symptoms in Wilson Disease

abstract

Wilson disease (WD) is an autosomal-recessive disorder of hepatic copper metabolism that has tremendous variability in its presenta-tion. Phenotypic diversity of the disease can lead to delayed diagnosis. We describe a case of WD in a 10-year-old boy presenting with 3 months of increasingly intense, spasmodic lower extremity muscle cramps. Physical examination revealed tenderness on calf palpation and darkflat lesions over his ankles, knees, and elbows. Initial testing revealed creatine kinase of 302 IU/L (normal 24–248 IU/L), hemoglobin of 8.9 g/dL (11.5–15.5 g/dL), aspartate aminotransferase of 114 IU/L (16–52 IU/L), alanine aminotransferase of 54 IU/L (2–30 IU/L), and myoglobinuria. Extensive evaluation of his myopathy, including MRI and muscle biopsy, was negative. Additional laboratory tests revealed a prothrombin time of 21.3 seconds (11.8–15.5 seconds), total biliru-bin of 1.4 mg/dL (,1 mg/dL), direct bilirubin of 0.5 mg/dL (,0.3 mg/ dL), albumin of 2.1 g/dL (3.1–4.6 g/dL), a reticulocyte percentage of 4.5% (0.5%–2.5%), a negative Coombs direct antibody test, ceruloplas-min of 3 mg/dL (21–51 mg/dL), and 24-h urine copper of 393mg/24 h (15–60mg/24 h). Liver biopsy showed patchy advancedfibrosis, mild inflammation, positive staining for copper, and a tissue copper con-centration of 768mg/g (10–35 mg/g). Brain MRI revealed symmetric intrinsic T1 shortening within bilateral basal ganglia. Trientene ther-apy was initiated for WD. Symptoms and laboratory abnormalities resolved and remain normal at 21 months’follow-up. Musculoskeletal involvement in WD is uncommon and typically defined as bone de-mineralization, arthropathy, or hypokalemic muscle weakness. In patients with unexplained musculoskeletal symptoms and hepatic abnormalities, a diagnosis of WD should be considered and appropri-ate evaluation initiappropri-ated.Pediatrics2013;132:e1039–e1042

AUTHORS:John M. Rosen, MD,a_{Nancy Kuntz, MD,}a_Hector

Melin-Aldana, MD,a,b_{and Lee M. Bass, MD}a

Departments ofa_{Pediatrics and}b_{Pathology, Ann & Robert H. Lurie}

Children’s Hospital of Chicago, Chicago, Illinois

KEY WORDS

musculoskeletal pain, rhabdomyolysis, liver disease, metabolic diseases/disorders

ABBREVIATIONS

KF—Kayser-Fleischer WD—Wilson disease

Dr Rosen collected primary data and drafted and revised the manuscript; Dr Kuntz collected primary data and reviewed and revised the manuscript; Dr Melin-Aldana performed and interpreted histopathological tests and reviewed and revised the manuscript; Dr Bass conceptualized the study and reviewed and revised the manuscript; and all authors approved theﬁnal manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2012-2923

doi:10.1542/peds.2012-2923

Accepted for publication May 28, 2013

Address correspondence to John M. Rosen, MD, Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108. E-mail: jmrosen@cmh.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

FINANCIAL DISCLOSURE:The authors indicated they have no

ﬁnancial relationships relevant to this article to disclose.

FUNDING:No external funding.

POTENTIAL CONFLICT OF INTEREST:The authors have indicated they have no potential conﬂicts of interest to disclose.

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Wilson disease (WD), or progressive hepatolenticular degeneration, is a phenotypically variable autosomal-recessive disorder of hepatic copper metabolism. In this case report we describe a 10-year-old boy with WD who initially presented with muscle spasm and mildly elevated aminotransferases. This atypical presentation, and symp-tom resolution with chelation therapy, highlights the varied chief complaints of WD and the importance of screening tests to assist in early and accurate diagnosis.

PATIENT PRESENTATION

A 10-year-old boy presented with 3 months of increasingly intense spas-modic lower extremity muscle cramps. The cramps caused pain that radiated from his calves to his thighs, lower back, and right shoulder. The patient complained of fatigue and mild weak-ness but had no other systemic symptoms, including fever, arthritis, or change in cognitive function. Physical examination revealed tenderness on calf palpation and darkﬂat lesions over his ankles, knees, and elbows. Initial testing revealed the following: creatine kinase of 302 IU/L (normal 24–248 IU/L), hemoglobin of 8.9 g/dL (11.5–15.5 g/dL), mean corpuscular volume of 74 fL, a red blood cell count of 4.23106/mL (4.0–5.2 106/mL), an erythrocyte sedimentation rate of 44 mm/hour (0–20 mm/hour), aspartate aminotransferase of 114 IU/L (16–52 IU/L), alanine aminotransferase of 54 IU/L (2–30 IU/L), g -glutamyl-transferase of 47 IU/L (8–55 IU/L), alka-line phosphatase of 303 IU/L (90–300 IU/L), serum potassium of 3.8 mEq/L (3.7–5.5 mEq/L), serum uric acid of 3.4 mg/dL (2–7 mg/dL), serum CO2of 22.6 mEq/L

(23–30 mEq/L), urine pH of 5.5 (pH 5–8), glucosuria, and myoglobinuria. Family history was positive only for a sibling with autism spectrum disorder. The patient was taking no medications or

supplements and reported no recent illness or injury.

Three months after initial presentation, laboratory tests revealed a prothrombin time of 21.3 seconds (11.8–15.5 sec-onds), total bilirubin of 1.4 mg/dL (,1 mg/dL), direct bilirubin of 0.5 mg/dL (,0.3 mg/dL), albumin of 2.1 g/dL (3.1–4.6 g/dL), reticulocyte percentage of 4.5% (0.5%–2.5%), and a negative Coombs direct antibody test. A ferritin level of 11 ng/mL (22–322 ng/mL) and a soluble transferrin receptor concen-tration of 132 nmol/L (8.8–28.1 ng/mL) indicated iron deficiency due to de-pletion through hyperactive erythropoi-esis or secondary to hepatic disease that reduced the ability to store iron. Anemia with an elevated reticulocyte percentage, a red cell distribution width of 22% (12.5%–16%), and a mean cor-puscular hemoglobin concentration of 28 g/dL (31–37 g/dL) suggested red blood cell hemolysis or loss with in-effective erythropoiesis. Serum amino acid (multiple elevations) and urine or-ganic acid (tyrosyluria) screening was nonspecific. Intermittent minor ele-vations of creatine kinase, in the setting of myalgia and exercise intolerance, raised the possibility of metabolic my-opathy. Serum levels of glucose 6 phosphate dehydrogenase, glutathi-one, phosphofructokinase, phospho-glycerate kinase, and triosephosphate isomerase were normal. Skin fi bro-blast culture for fatty acid oxidation studies revealed no abnormalities. Ab-dominal ultrasound with Doppler, lower extremity MRI, and muscle bi-opsy of the left vastus lateralis,

in-cluding electron microscopy and

extensive immunostaining, were nor-mal. WD was not considered at this time, and ceruloplasmin was not sent. A skin biopsy of hyperpigmented lesions revealed a superﬁcial peri-vascular lymphohistiocytic inﬁltrate. Bone marrow aspiration and biopsy showed moderately hypercellular

marrow with focal necrosis, adequate megakaryopoiesis, and hypochromic microcytic anemia.

Over the next 3 months, the patient developed worsening muscle cramps and new bilateral nonpitting lower ex-tremity edema. Brief, recurrent, severe cramps involving his forearms, hands, face, neck, anterior chest, and thighs occurred multiple times daily and lim-ited activity. He remained ambulatory and functionally independent. Oph-thalmologic examination revealed Kayser-Fleischer (KF) rings and

sun-ﬂower cataracts. Serum ceruloplasmin was 3 mg/dL (21–51 mg/dL) and 24-h urine copper was 393mg/24 h (15–60

mg/24 h). Liver biopsy showed patchy advanced ﬁbrosis, mild inﬂammation, positive staining for copper, and an elevated tissue copper concentration of 768 mg/g (10–35 mg/g). Post-operatively, the patient developed rhabdomyolysis (elevation in creatine kinase [55 904 IU/L] and aldolase [15.6 U/L]) that responded to symptomatic treatment. Rhodanine staining of the muscle biopsy was negative for copper deposition. Brain MRI with spectros-copy revealed symmetric intrinsic T1 shortening within bilateral basal gan-glia (most prominently globus pal-lidus).

Selected images of the patient’s muscle biopsy (hematoxylin and eo-sin, rhodanine, cytochrome oxidase stains), liver biopsy (hematoxylin and eosin, rhodanine stains), KF rings, sunﬂower cataracts, brain MRI, and skin lesions are included in Supple-mental Figures 1–5.

Therapy with trientene was initiated to treat WD. Muscle cramps, weakness, and most laboratory abnormalities resolved within 2 months of treatment. Prothrombin time normalized within 8 months. The patient remained symptom-free with normal aminotransferases, albumin, and prothrombin time at 21-month follow-up. The patient’s brother

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was screened for WD due to his cog-nitive and behavioral disorder, with results of a ceruloplasmin concentra-tion of 21 mg/dL (21–51 mg/dL) and a 24-h urine copper level of 10mg/24 h (15–60mg/24 h).

DISCUSSION

WD is a chronic disorder of copper metabolism with a worldwide average prevalence of 1 in 30 000. Despite identiﬁcation of the sole mutated gene, ATP7B, and increased understanding of Wilson disease ATPase function in hepatocytes, associations between ge-netic mutation and clinical phenotype remain incompletely understood.1–3

Liver dysfunction in WD ranges from mild aminotransferase elevation to fulminant hepatic failure. Extrahepatic

ﬁndings, with or without apparent liver injury, including neuropsychiatric, en-docrine, hematologic, and renal ab-normalities, result in a complex clinical spectrum that may lead to delayed or inaccurate diagnoses. Advanced he-patic and neurologic sequelae of WD may be prevented by early disease identiﬁcation and initiation of treat-ment.

Serum ceruloplasmin and basal 24-h urinary copper excretion, without the immediate need for genetic analysis, effectively identify most pediatric patients with WD.4,5 _Notably,

recom-mended pediatric screening thresh-olds of ceruloplasmin,20 mg/dL and 24-h urinary copper.40mg/24 h may vary from laboratory normative val-ues.5_{The case presented had several}

features associated with WD that were eventually identiﬁed (liver involvement, KF rings, Coombs-negative hemolytic anemia, basal ganglia abnormalities), but the chief complaint of muscle spasm misdirected initial evaluation. Hyperpigmented anterior leg lesions are reported in WD, but they are characterized by increased basal layer

melanin deposition that was not pres-ent in this case.6

Muscle spasm and rhabdomyolysis are not included as presenting symptoms of WD in textbooks or in national guidelines. Reports of musculoskeletal symptoms are mainly limited to bone deminer-alization, arthropathy,7 _and

hypokale-mic muscle weakness.8,9

A case series abstract reported 26 WD patients, 19 with varied arthritis, and 8 with muscle cramps.10 _{Most of these}

patients were receiving the chelator penicillamine, a known cause of im-munologically induced inﬂammatory myopathy.11 _{Musculoskeletal}

involve-ment in WD may be more common in those of Indian ethnicity, which did not apply to our patient. A study in Mumbai identiﬁed“osseomuscular”ﬁndings in 20 of 30 (66%) WD patients including 8 with recurrent joint pain initially dis-missed as growing pains.12 _Another

study of WD patients in Bangalore found osseomuscular features in 37 of 282 (13%) patients, all with arthralgia, 6 with arthritis, and 22 with proximal weakness resembling myopathy.13

Neither myalgia nor rhabdomyolysis were described in patients of either study.

One case report in a 17-year-old male with WD included a history of muscle pain, weakness, KF rings, and decom-pensated cirrhosis at presentation.14

Initial muscle pain was not character-ized, and recurrent acute

rhabdo-myolysis occurred subsequent to

penicillamine therapy. Increased tissue copper on muscle biopsy suggested that at least a component of myopathy or rhabdomyolysis was related to WD and not to therapy. In our patient, muscle copper staining was negative and muscle parenchymal copper con-centration was not measured.

Copper toxicity preferentially affects red blood cells, hepatocytes, and myo-cytes. Numerous reported cases of copper sulfate toxicity, both acute and

chronic, manifest with rhabdomyol-ysis.15_–17 _{Additionally, copper}

experi-mentally inhibits the Na+/K+ATPase on cellular membranes and increases permeability.18_{Copper is a cofactor of}

many enzymatic reactions, and there may be other undiscovered mecha-nisms of cellular injury.

Copper toxicity of skeletal muscle is the likely cause of muscle cramping and rhabdomyolysis in this case. Although staining of the patient’s muscle biopsy sample for tissue copper was negative, it is not clear that copper deposition is required for copper-induced myopathy. Cirrhosis, through an unknown mech-anism, is also associated with muscle spasm. However, chelation therapy, which resolved symptoms in this case, has no effect on extent of cirrhosis. This patient never had signiﬁcant se-rum electrolyte abnormalities (sese-rum potassium of 3.5–4.6 mEq/L) that con-tributed to muscle weakness or injury. Centrally mediated muscle spasm and weakness are possible, but basal gan-glia abnormalities could not account for rhabdomyolysis. This patient’s exacerbation of rhabdomyolysis sub-sequent to succinylcholine

adminis-tration suggests that alternate

paralytic agents should be considered in WD patients.

This case report identiﬁes a phenotypic presentation of WD that includes mus-cle spasm and mild liver disease. Given the known mechanism of copper tox-icity on myocytes, WD should be con-sidered in the diagnosis of all children with unexplained musculoskeletal symp-toms and hepatic abnormalities. A low threshold should exist to perform noninvasive screening of serum ceru-loplasmin levels and basal 24-hour urinary copper excretion.

ACKNOWLEDGMENT

The authors thank Dr. Steven Hall for discussion of anesthesia in patients with myopathy.

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S, Gnanathasan A, Puvanaraj V, Fernando H. Complications and management of acute copper sulphate poisoning; a case discus-sion.J Occup Med Toxicol. 2011;6(1):34 16. Hassan S, Shaikh MU, Ali N, Riaz M. Copper

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e1042 ROSEN et al

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DOI: 10.1542/peds.2012-2923 originally published online September 2, 2013;

2013;132;e1039

Pediatrics

John M. Rosen, Nancy Kuntz, Hector Melin-Aldana and Lee M. Bass

Disease

Spasmodic Muscle Cramps and Weakness as Presenting Symptoms in Wilson

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DOI: 10.1542/peds.2012-2923 originally published online September 2, 2013;

2013;132;e1039

Pediatrics

John M. Rosen, Nancy Kuntz, Hector Melin-Aldana and Lee M. Bass

Disease

Spasmodic Muscle Cramps and Weakness as Presenting Symptoms in Wilson

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