Four-year follow-up of a Wilson disease pedigree complicated with epilepsy and hypopituitarism: Case report with a literature review.

RATIONALE: Wilson's disease (WD) is an autosomal recessive inherited disorder of copper metabolism with excellent prognosis if treated timely. However, WD is usually prone to neglect and misdiagnosis at an early stage. We reported a rare WD pedigree, and the clinical features, laboratory tests, and gene mutations were analyzed in detail. PATIENT CONCERNS: The patient was a 17-year-old and 136-cm-tall girl who presented with limb weakness, combined with multi-organ disorders including blind eye, epilepsy, and hypopituitarism. DIAGNOSES: Clinical tests showed a low serum ceruloplasmin level, high urinary copper excretion and Kayser-Fleischer (K-F) rings. She carried a compound heterozygous mutations in ATP7B gene (c.2828G>A and c.3884C>T). Her younger brother, as an asymptomatic patient, manifested with elevation of transaminases but without neurological and hepatic symptoms. They were diagnosed as WD finally.
INTERVENTIONS: They were treated with sodium dimercaptosulphonate, supplemented with zinc gluconate, vitamin B6, vitamin C, as well as restriction of dietary copper. OUTCOMES: The urinary copper excretion and serum transaminase level decreased gradually. The abnormal signals in brainstem and basal ganglia were also remarkably decreased after 4-year of de-copper treatment. LESSONS: As to the patients with complicated clinical manifestations, the extrapyramidal symptom and basal ganglia signals should be concerned. The serum ceruloplasmin detection and ATP7B gene mutation screening are necessary.

Introduction

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism with a prevalence of 1 in 30,000 and a carrier frequency of 1 in 150 to 180.[ The disease-causing gene, ATPase copper transporting beta (ATP7B), maps to 13q14.3 and encodes a transmembrane protein ATPase (ATP7B). Clinically, majority of WD patients are young adults characterized by extrapyramidal symptoms, hepatic cirrhosis, Kayser–Fleischer (K–F) rings, low serum ceruloplasmin level (<50 mg/L), and high 24-hour urinary copper excretion (>100 μg/L).[ As an inherited neurological disease, encouragingly, WD has an excellent prognosis if the patients could be diagnosed at early stage and treated timely.[ However, to those patients who are atypical clinically and accompanied with complex medical history simultaneously, WD is usually easy to be neglected and misdiagnosed. Here, we report an early and atypical WD pedigree.

Case presentation

The proband was a 17-year-old and 136-cm tall female patient, who was transferred to our hospital complaining of progressive weakness in left limbs over 3 months. First, weakness was noted in left side lower limb giving rise to difficulty in stepping forward. Without seeking any medical treatment, this manifestation progressed gradually to disability in walking, complicated with mild dysarthria, without disturbance of consciousness, muscular fasciculation, myodynia and muscular atrophy, without nausea, vomiting, abdominal pain, distension, and jaundice. Besides, she had a complex medical history. Aged 2 months, her left eye became completely blind due to an ocular infection. At the age of 2 years, she suffered from recurrent unconsciousness and convulsion of limbs. Her parent described that she showed a cry first and then presented with loss of consciousness, foaming at the mouth, tonic contractions of limbs, and urinary incontinence sometimes. These symptoms occurred suddenly and lasted about 1 to 2 minutes. The frequency was about 1 to 2 times/mo at first and it reduced gradually after antiepilepsy treatment (valproate and phenobarbital) and no seizures occurred after 7 years old. In our department, the electroencephalogram test was performed, and only mild abnormal α waves were observed on occipital region, while no remarkable sharp waves or spike waves were detected (Supplemental figure 1). At the age of 10 years, she developed a slow stature growth, and further investigation indicated that she suffered from empty sella syndrome. Since youth, she also showed an ill tolerance of sports.

The significant physical examination included mild dysarthria, slight intelligent decline (mini–mental state examination [MMSE]: 28 scores; Montreal Cognitive Assessment [MoCA]: 25 scores), developmental delay, short stature, rudimentary breast, and genitals. The neurological examination showed muscle hypertonia in left limbs, and muscle power was decreased (grade 4). Brain magnetic resonance images (MRIs) showed mild cerebral atrophy, significant atrophy in left side of eye (Fig. 1A) and an empty sella (Fig. 1B). Further investigation revealed low level of serum hormones, including growth hormone (0.9158 mg/mL), adrenocorticotropic hormone (08:00, 1.57 pg/mL and 16:00, 1.33 pg/mL), cortisol (08:00, 0.111 μg/dL and 16:00, 1.33 μg/dL), follicle-stimulating hormone (1.07 mIU/mL), luteinizing hormone (0.000 mIU/mL), estrogen (24.78 pg/mL), progesterone (0.19 ng/mL), testosterone (27.36 mg/dL), and prolactin (19.52 ng/mL). She had only 8 years of bone age.

Figure 1

Comparison of brain magnetic resonance image of the proband before (A–C) and after (D–I) decopper treatment. (A) The left side of eye showed significant atrophy. The abnormal signals in brain stem were scanned. (B) The empty sella was observed. (C) The abnormal signals in basal ganglia were observed on T2-weighted image. (D) and (F)–(I) The abnormal signals on brain stem and basal ganglia were decreased significantly after decopper treatment. (D) and (F) T2-weighted image, (G) fluid-attenuated inversion recovery sequence, (H) susceptibility weighted image, and (I) apparent diffusion coefficient image. (E) The empty sella was not changed remarkably after decopper treatment 4 years later. Arrows indicate the lesions.

Based on ill tolerance of sports, developmental delay, short stature, and progressive limb weakness, she got a tentative diagnosis of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), which is a common genetic disorder with ischemic stroke among the young individuals, and 80% of the affected carry A3243G mutation in mitochondrial deoxyribose nucleic acid (mtDNA). After treating with vitamin B, coenzyme-10, and hydrocortisone, improvement in limb weakness was present but fluctuant. Besides, her serum lactic acid was normal (resting lactic acid, 1.6 mmol/L; Glucose-loading lactic acid, 2.3 mmol/L). After admitting to our department, a fast screening of A3243G mutation was performed, the result was negative (data not shown). Electromyography (EMG) tests were also performed including motor nerve conduction, sensory nerve conduction, needle EMG, F waves, and H reflex, which showed that no neurogenic or myogenic damages were detected. Taken together, the evidence for MELAS was not sufficient.

To further seek the underlying reason for this patient, we recalled her medical records and abnormal signals in brainstem (Fig. 1A), and basal ganglia were noted (Fig. 1C). Besides, ocular examination revealed K–F rings on her right cornea (Fig. 2A), which promoted us to seek more evidence for WD. The copper metabolism investigation revealed an extremely low ceruloplasmin level (21.80 mg/L; NR, 200–600 mg/L), a low concentration of serum copper (5.94 μmol/L; NR, 12.7–30.2 μmol/L), and a high 24-hour urinary copper excretion (193.04 μg/d; NR, 0–125 μg/d). Abdominal ultrasound test was normal, without any evidence of cirrhosis and hepatosplenomegaly. We further screened the mutation in ATP7B gene by Sanger sequencing and found a compound heterozygous mutations (c.2828G > A [p.G943D] and c.3884C > T [p.A1295V]) (Fig. 3A).

Figure 2

Kayser–Fleischer (K–F) rings were found on the cornea of the proband and her younger brother. (A) The proband, (B) her younger brother, (C) her father, and (D) her mother. Arrows indicate the K–F rings.

Figure 3

The mutation analysis of this Wilson disease pedigree. The c.2828G > A and c.3884C > T mutations were detected in ATP7B gene by Sanger sequencing. (A) The proband, (B) her younger brother, (C) her father, and (D) her mother.

After the confirmed diagnosis of WD, her parents were worried about their 12-year-old son, who was normal in development, without muscle weakness, atrophy, and myalgia. K–F rings were also observed (Fig. 2B). The laboratory tests revealed elevation of transaminases, with alanine aminotransferase (ALT) 139 U/L (NR, 5–50 U/L) and aspartate aminotransferase (AST) 98 U/L (NR, 8–40 U/L), as well as a decreased ceruloplasmin (39.7 mg/L). No significant images were found on abdominal ultrasound and brain MRI. He also carried the same missense mutations in ATP7B gene (Fig. 3B). Their parents were normal without any symptoms at their 40s. Their liver function and ceruloplasmin level were normal (ALT 22 U/L, AST 22 U/L, and ceruloplasmin 275 mg/L for the father; ALT 19 U/L, AST 22 U/L, and ceruloplasmin 307 mg/L for the mother). No K–F rings were observed (Fig. 2C and D). Further genetic testing showed that the c.2828G > A (p.G943D) mutation was transmitted from the father and the c.3884C > T (p.A1295V) mutation was transmitted from the mother (Fig. 3C and D).

To this early stage of WD pedigree, the timely treatment is critical. With informed consent, the patient began to accept decoppering treatment with sodium dimercaptosulphonate 187.5 mg (5 mg/kg) daily for 5 days as a course and 8 courses in total, supplemented with zinc gluconate, vitamin B6, vitamin C, as well as restriction of dietary copper. In the following years, dimercaptosulphonate was substituted by dimercaptosuccinic acid (0.25 mg, bid) and zinc gluconate. Her dysarthria and limb weakness improved gradually, and she could talk fluently and walk unaided. The muscle tension and power were normal (grade 5). She still showed development delay; she is 136 cm tall at the age of 21 years. MMSE (28 scores) and MoCA (25 scores) tests were not changed significantly. Her urinary copper excretion per 24 hours has been reducing to a stable low level gradually; but the serum ceruloplasmin still maintains at a low level (Fig. 4A and B). The serum hormone testing showed that the gonadal hormones still sustain in a low level, and growth and adrenocorticotropic hormones were normal (growth hormone [1.17 mg/mL], adrenocorticotropic hormone [08:00, 21.33 pg/mL], cortisol [08:00, 16.64 nmol/L], follicle-stimulating hormone [0.430 mIU/mL], luteinizing hormone [0.150 mIU/mL], estrogen [<18.35 pmol/L], progesterone [<0.095 nmol/L], and testosterone [<0.087 nmol/L]). The empty sella was not changed significantly on MRI images (Fig. 1E). However, the abnormal signals in brainstem and basal ganglia were remarkably decreased after 4 years of decopper treatment (Fig. 1D and F–I). To her younger brother, as an asymptomatic individual, restriction of dietary copper was advised, as well as supplement with zinc gluconate. His serum transaminase levels have also been reducing gradually, while the serum ceruloplasmin did not change significantly either (Fig. 4C and D).

Figure 4

The following up clinical profiles of this Wilson disease pedigree. The urinary copper excretion (A) and serum ceruloplasmin level (B) for the proband. The serum transaminases (C) and ceruloplasmin level (D) for her younger brother.

Discussion

As a copper metabolism disorder, pathological accumulation of copper in the liver, brain, and cornea ultimately leads to liver disease, neurologic symptoms, and ophthalmological involvement. However, clinical presentation of WD can be variable, ranging from pure liver disease to conditions that limited to the central nervous system.[ Usually, patients with hepatic dysfunction as their initial symptoms tend to show an earlier onset of symptoms than those with a neurologic presentation.[ Extrapyramidal manifestations, including chorea, tremor, and dystonia, are the most common neurological presentations.[ In this pedigree, the patient presented with atypical neurological symptoms of limb weakness and mild dysarthria, which may lead to a misdiagnosis of stroke. WD cases with stroke-like presentation were also reported before.[ In addition, this case of WD also combined with epilepsy and hypopituitarism. Presentation of epilepsy in patients of WD has been reported,[ and the prevalence of epilepsy in WD was 10 times higher than that in general population.[ It is more likely that copper deposition in the brain is responsible for most of the epilepsies. However, the hypopituitarism of this case seemed not be associated with WD, because the serum hormones and empty sella on brain MRI were not changed significantly after effective decopper treatment 4 years later.

In this report, the patient's younger brother mainly presented with isolated elevation of aminotransferases and no clinical symptoms. According to previous study, asymptomatic elevation of aminotransferases was a common onset of manifestations in pediatric patients, which may largely delay WD diagnosis.[ Fortunately, genetic testing in our lab confirmed the diagnosis of WD for this asymptomatic patient. Although previous study concluded that isolated elevation of serum aminotransferases indicated a benign condition,[ follow-up is still needed when detected incidentally in children. In addition, a measurement of serum ceruloplasmin and urine copper may have diagnostic value for the screening of WD in these children.[ Besides, for these patients, early diagnosis and timely intervention are most essential to prevent permanent damage to the liver and progression in the brain.[

In the aspect of treatment, fortunately, WD is a condition that can be effectively treated, and those adequately treated usually have a normal life span. Penicillamine, dimercaprol, zinc acetate, and other treatments have been used successfully as decoppering therapy or as preventative therapy in presymptomatic patients. In this WD pedigree, both of the patient and her younger brother showed well response to decopper treatment, with decreased urinary copper excretion and serum transaminase level in the follow-up period, and the serum ceruloplasmin maintained in a stable level. Besides, the abnormal signals in brainstem and basal ganglia were also remarkably decreased, which was presumed to be associated with the excretion of cranial copper.

Interestingly, the concurrence of limb weakness, intolerance of sports, developmental delay, and short stature made it confused with MELAS initially; however, the negative result of mtDNA A3243G mutation, combined with the normal serum lactic acid level and no myogenic damages on EMG test, argued against this primary diagnosis. Under such circumstances, the molecular testing of mtDNA and ATP7B gene mutation seems to be necessary and important. To date, more than 600 distinct disease-causing mutations have been reported in ATP7B gene (http://www.hgmd.org/), and the majority of WD patients are compound heterozygotes. According to Dong et al[ research, the c.2828G > A (p.G943D) mutation was one of the common disease-causing variants in Chinese WD patients. If possible, direct sequencing of the whole ATP7B gene is advised, and the high-throughput next-generation sequencing is also a reliable and time-saving method for diagnosing WD.[

In conclusion, we reported an early and special WD pedigree with c.2828G > A and c.3884C > T mutations in ATP7B gene, and we hope that it will facilitate the understanding, diagnosis and treatment of WD to neurologist, ophthalmologist, and endocrinologist. For atypical pediatric patients, especially with asymptomatic elevations of aminotransferases, the routine serum ceruloplasmin detection is necessary, which will help to diagnose WD at early stage and treat at presymptomatic stage.