Clinical Reasoning: A 24-year-old man with head tremor and decreased ceruloplasmin level

Section 1

A 25-year-old Chinese man had developed involuntary and irregular head tremor with no triggers at the age of 18 years. The head tremor occurred intermittently at first with a frequency of several times per week lasting from several minutes to up to an hour. His head tremor worsened progressively and became persistent at age 24 years. It was aggravated by exercise and emotional stress, relieved by relaxation and alcohol, and disappeared during sleep. He denied a family history of tremor. An initial diagnosis of essential tremor was made and he was referred to our department. Neurologic examination revealed mild cerebellar dysarthria, diffuse hyperreflexia, a “no-no” head tremor, and mild torticollis. The amplitude of the patient's head tremor was increased when he turned his head leftward and decreased when he turned rightward (video 1). Dysdiadochokinesia and minimally impaired tandem walking were also observed. Other neurologic examination findings included absence of gaze-evoked nystagmus, normal eye movements (saccades and smooth pursuit), and normal finger-nose and heel-to-shin tests.

Section 2

Head shaking without ataxia or torticollis was present at the initial presentation. The patient subsequently developed focal, action-type tremor that was irregular both in amplitude and rhythm and persisted in the supine position. The tremor was exacerbated by head turn away from dystonic posturing of the neck, and abated by head turn toward the dystonic neck posture (e.g., null point). The above features suggested the head tremor to be a dystonic tremor. Neurologic examination disclosed mild ataxia. For these reasons, a diagnosis of dystonia-ataxia syndrome was considered. The spectrum of genes associated with dystonia-ataxia syndrome are currently expanding with the development of next-generation sequencing¹; more than 100 genetic disorders can present with dystonia-ataxia syndrome, including hereditary ataxias such as spinocerebellar ataxias (SCAs) and autosomal recessive ataxias, neurodegeneration with brain iron accumulation such as aceruloplasminemia, Wilson disease (WD), and others.

Of these diseases, WD is treatable and should be considered and evaluated, especially in cases of juvenile onset. We therefore performed ceruloplasmin level and found it to be moderately reduced (126 mg/L; normal 210–530 mg/L). Levels of serum copper, urine copper, and serum ferritin were normal.

Ophthalmologic examination did not demonstrate Kayser-Fleischer rings or retinal degeneration. Brain MRI showed mild atrophy of the cerebellum (figure, A). The prominent juvenile-onset extrapyramidal signs and decreased ceruloplasmin was suggestive of a diagnosis of WD, while the normal urinary copper and absence of Kayser-Fleischer rings were not. To further exclude the diagnosis of WD, we screened the ATP7B gene and detected no mutation. Since ceruloplasmin is encoded by the CP gene, we performed a genetic analysis of CP, which elucidated a heterozygous mutation (c.2158C>T, p. Arg720Trp) (figure, D). Pedigree analysis revealed that the patient's 62-year-old father carried the same heterozygous mutation in CP (figure, D). His mother had died of cancer.

• Download figure
• Open in new tab
• Download powerpoint

Figure MRI and electropherogram

(A) Sagittal T2-weighted MRI of the proband showing mild cerebellar atrophy. (B) Sagittal T2-weighted MRI of the proband's father showing moderate cerebellar atrophy. (C) Axial susceptibility-weighted imaging of the proband showing no iron deposition in the basal ganglia. (D) Electropherogram of a heterozygous CP c.2158C>T (p. Arg720Trp) mutation of the proband and his father. (E) Electropherogram of a heterozygous PRKCG c.431-457del (p. Arg144-Asp153delinsHis) mutation of the proband and his father.

Section 3

Aceruloplasminemia is a rare autosomal recessive disorder characterized by diabetes, retinal degeneration, and neurodegenerative manifestations caused by biallelic mutation of CP, leading to an absence of serum ceruloplasmin and subsequent iron accumulation in the brain, liver, and pancreas.² Previous studies have reported that patients with hypoceruloplasminemia caused by heterozygous mutation of CP can present with neurologic symptoms—mostly cerebellar and extrapyramidal signs—with normal serum ferritin and the absence of diabetes or retinal degeneration.^3,–,5 Among these cases, a 16-year-old girl presenting with ataxia, involuntary movement of the right leg, and reduced ceruloplasmin level (100 mg/L) carried the same heterozygous mutation as our patient⁴; her father was asymptomatic, but he exhibited a decreased ceruloplasmin level (130 mg/L) and carried the same mutation.⁴

Given that our patient's father carried the same heterozygous mutation in CP, we tested his father's serum ceruloplasmin level and found it to be decreased (189 mg/L). The father's level of serum ferritin and glycated hemoglobin were normal. Further neurologic examination of the father revealed abnormal neurologic signs that had not been noticed before, including moderate cerebellar dysarthria, limb and trunk ataxia, and an ataxic gait. His brain MRI showed moderate atrophy of the cerebellum (figure, B).

Section 4

Although heterozygous mutation of CP is reported in several cases to cause symptoms, the association remains controversial. A total of 10 articles have reported hypoceruloplasminemia in 26 individuals with heterozygous mutations of CP. Of these cases, only 6 presented with neurologic symptoms (e.g., cerebellar and extrapyramidal signs).⁵ Prior cases have included ATP7B screening in addition to CP to exclude the diagnosis of WD.⁴ Another case study reported a father and his son who presented with slowly progressive cerebellar ataxia and a decreased ceruloplasmin level. A heterozygous mutation of CP (c.2630 G>A, p. Trp858ter) was detected, and a diagnosis of hypoceruloplasminemia was rendered after excluding SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and dentatorubral-pallidoluysian atrophy with short tandem repeat (STR) analysis.³ However, the possibility of a concomitant SCA caused by non-STR could not be excluded.

Because our patient's father also had ataxic symptoms, we screened with STR analysis for SCAs but did not find any abnormal expansions. To further evaluate whether our patient and his father had causative mutations in other genes, whole exome sequencing (WES) was performed and a heterozygous mutation (c.431-457del, p. Arg144-Asp153delinsHis) in exon 5 of the protein kinase C gamma gene (PRKCG) was detected (figure, E), indicating a diagnosis of SCA14. The mutation was not found in the 1,000 Genomes Project or the Human Genetic Variation Database and was considered to be likely pathogenic according to criteria of the Standards and Guidelines for the Interpretation of Sequence Variant.