Case Report ovement Disorder with Abnormal Copper Metabolism -ACaseReport and Review of the Literature

dysarthria, involuntary movements, spastic low serum copper, borderline low to normal serum ceruloplasmin, normal urinary copper, and a high hair copper concentration. This neurological disorder appears to differ from others associated with abnormal copper metabolism such as Wilson's or Menkes' kinky hair disease.

It is well known that Wilson's disease (1) and Menkes' kinky hair disease (2) are neurological disorders caused by abnormal copper metabolism. There are also rare cases of neurological diseases with abnormal copper metabolism including spinocerebellar degeneration (3) and torsion dystonia (4). However, there have been few reports on unusual neurological disorders with abnormal copper metabolism (5-1 1).
We describe a neurological disease with dysarthria, involuntary movements, spastic gait and high hair copper concentration.

CASE REPORT
A 22-year-old womanpresented with involuntary movements and a gait disturbance.
She was the elder of identical twins. She was born at full term after a normal pregnancy and delivery, body weight at birth was 2.2 kg. There was no parenteral consanguinity or family history of neurological diseases. She learned to walk at the age of 2 yr. At about 4-yrold, she experienced the insidious onset of involuntary movements in the face, neck and all four extremities, along with dysarthria and a gait disturbance which developed slowly and progressively. These symptoms progressed until the age of about 6 yr, at which time they stabilized.
She Ceruloplasmin was measured by the Houchin method (12). Serum and urine copper were measured by the Meret and Henkin method (13) and tissue copper by a colorimetric method modified from that of Eden and Green (14). Hair samples were washed with shampoo, purified water, and acetone, and then dried. These were then weighed, ashed and measured by flameless atomic absorption spectroscopy (15).
The serum copper level was slightly low (75 g/dl), but urinary copper and CSF copper were normal (23^g/dl, 3 #g/dl, respectively). Serum ceruloplasmin was normal (20 mg/dl). Serum copper was slightly low, and serum ceruloplasmin was borderline low to normal during the last three yr. Biopsied specimens of the liver and rectal mucosa showed normal histology, and the former was negative for copper by orcein and rubeanic acid stains. The liver copper level was normal (3 1.3^g/g dry wt). The rectal mucosa copper level was slightly low (30.8 fxg/g dry wt). The hair copper level was high (122 /ig/g dry wt; normal 16-59 / ig/g dry wt).
The patient's younger twin had a serum copper, urinary copper, and serum ceruloplasmin level of 102 //g/dl, 20 /*g/day and 22 mg/dl, respectively. Her hair copper level was high (138.6^g/g dry wt). However, she had no neurological symptoms. The patients mother had a serum copper, urinary copper and serum ceruloplasmin level of 75^g/dl, 20 /ig/day and 25 mg/dl, respectively, and her hair copper was normal (55.5 (ag/g dry wt). The younger twin and mother revealed normal blood cell counts and blood biochemistries.
The father of this patient was unavailable for evaluation. These findings suggest that this family has a possible abnormal copper metabolism.

DISCUSSION
Typical neurological disorders with abnormal copper metabolism have been described in Wilson's disease (1) and Menkes' kinky hair disease (2). Wilson's disease is inherited as an autosomal recessive trait and its clinical features include extrapyramidal symptoms, a Kayser-Fleischer ring, liver cirrhosis, low serum copper, low serum ceruloplasmin, high urinary copper and a high hepatic copper concentration. The pathophysiology suggested to be that of copper deposited in various organs, such as the liver, brain, cornea etc, by a decrease in copper excretion into the bile and ceruloplasmin biosynthesis.
Menkes' kinky hair disease is Though the present case has a familial occurrence for abnormal copper metabolism, it is impossible to diagnose Wilson's disease due to the absence of a Kayser-Fleischer ring, normal liver function, negative copper stains in the liver tissue, and normal urinary copper with/without penicillamine. Menkes' kinky hair disease is also ruled out from the patient's age, the absence of psychomotor retardation and seizures, normal hair and borderline low to normal serum copper and ceruloplasmin levels. The present case does not correspond to hereditary hypoceruloplasminemia or familial benign copper deficiency due to normal serum ceruloplasmin and copper levels in the younger twin and normal serum ceruloplasmin in the mother.
Recently, Ono and Kurisaki (8) (5)] and abnormal copper metabolism. Analyzing these reports, the age of onset is distributed from infancy to adulthood. The majority are sporadic cases, but two families had an X-linked recessive trait (5, 7) and the first case in a Wilson's family (9) is also reported.
Generally, it is said that copper deposition within the body is relatively highly concentrated in the following organs: the liver, kidney, heart, brain, hair, bone and skeletal muscles. Hambidge (18) concluded that exogenouscopper maycontribute to hair copper content, and that this results in a significant and progressive increase in the copper levels in the hair shaft with an increasing duration of exposure to copper in the external environment. After washing and drying, the hair samples were weighed, ashed and measured by atomic absorption spectrophotometry. Recently, Takagi (19) investigated various metals in human hair using flame or flameless atomic absorption spectroscopy, and reported that: 1) no significant age differences were observed pertaining to the amounts of copper, 2) female hair contained significantly more copper than male hair, and 3) there is a relatively high genetic correlation between both congenital twins and fraternal twins, but no genetic correlation between the twins and their parents or between other brothers and sisters. Similarly, weused highly sensitive, flameless atomic absorption spectroscopy and revealed high hair copper levels in this case and the younger twin.
There are three hypotheses regarding the pathogenesis of Wilson's disease: mutation of a single structural gene, a lysosomal defect, and mutation of a controller gene (20). The following pathogeneses of unusual neurological diseases with abnormal copper metabolism have been suggested: one is a genetic factor, two families with an X-linked recessive trait (5, 7) or heterozygotes in a Wilson's family (9), the other is an alternative error of copper metabolism (1 1), a defect of mucosal transport with a genetic factor (6) or intracellular binding without a genetic factor (10). In this case, the data showed an abnormal distribution of body copper resulting in a slightly low copper concentration in the serum and rectum and a normal concentration in the urine, CSF and liver, but with an accumulation in the hair despite the removal of an exogeneous factor. The m echanism remains unknown at present.
In conclusion, a family with abnormal copper metabolism and the case report of the elder identical twin who presented with dysarthria, involuntary movements, spastic gait, and a high hair copper concentration were described.