In a cohort of 517 unrelated families referred to the Kennedy Center in Denmark for genetic confirmation of MD, we found 10 manifesting carriers. One patient with 45X/46XX mosaicism has been described previously  and will not be described further here. Nine of the affected carriers, F1-F9, have normal karyotypes. The females were born in Europe (United Kingdom, France or Germany) or United States from 1969 to 2002. The clinical phenotypes of patients F1 and F2 have been described previously [4, 12].
Patient F1 (family, 9529) was born at 32 weeks gestation. Neonatally, sepsis and hyperbilirubinemia were suspected because of prematurity and a peculiar face was noted. At 31/2-4 months old: Ceruloplasmin: 0.14 g/l (normal: 0.15-0.60), S-Copper: 2 μmol/l (normal: 10-26 μmol/l). She had pneumonia, and was subsequently hospitalized several times due to other recurrent infections. She had stiff, coarse and pili torti hair, an enlarged liver and myoclonic jerks. The EEG was abnormal. At 5 years of age: Her motor development had reached the level of a 11/2-year-old child. She could only express single words, but her capacity for understanding language was better. A liver biopsy revealed a copper content in the lowest end of the normal range: 20 μg/g (normal: 20-45 μg/g), and an intestinal biopsy revealed an increased copper content: 47 μg/g (normal: 10-20 μg/g). Increased 64Cu uptake was observed in amniotic cells (from 16th week of gestation) and in fibroblasts when she was 4 years old: 52.3 ng 64Cu/mg protein/20 hours, (normal: 11.5-26.7 ng). Her brother suffered from classical MD and died at 6 months of age. Two heterozygous sisters (F1-S1 and F1-S2), both also born prematurely, had no symptoms of MD.
Patient F2 (family, 93232) was born at 38 weeks gestation. Neonatally, no problems were observed. At 11 months: She was hospitalized because of severe muscular hypotonia and failure to thrive. She had myoclonic seizures, tremor and ataxia, and suffered from orthostatic hypotension. The EEG revealed numerous rapid rhythmic waves and small 4- slow bilateral overlapping waves. Pili torti of the hair was noted at the time of the diagnosis, but is no longer present. She had left-sided talipes and osteoporosis. There were recurrent episodes of infections, especially otitis during childhood. The skin was dry and joints loose during infancy and childhood. Deafness was proved at the age of 2 years. Ceruloplasmin: 0.35 g/l (normal: 0.15-0.60), S-copper: 978 μg/l (normal: 850 - 1650 μg/l) at 5 years. Increased 64Cu uptake and retention in fibroblasts: 87.7 ng 64Cu/mg protein/20 hours and 66% retention, (normal: 11.5-26.7 ng uptake and 9.7-22.7% retention). During childhood and adolescence she went to a special-needs school, but her mental retardation remains significant. She is unable to read and write and does not have any language. She is not able to walk without aid but can walk a maximum of 50 meters with the help of a walker and requires assistance to use of a wheel-chair. Due to a dysmetry of the arms, self-feeding is difficult. At 34 years of age she lives in a center for disabled people. No copper treatment was given. There is, to our knowledge, no affected male in this family.
Patient F3 (family, 9228). In the first months of life, she suffered from frequent diarrhoea and motor development delay. MRI (at about 1 year) revealed cerebral and particularly cerebellar atrophy. She was unable to hold her head up at 7 months and unable to sit up at 14 months. The hair was sparse with pili torti. Copper histidine was administered when she was 21 months. Prior to treatment her psychomotor development was retarded, and she had significant feeding difficulties with loss of weight. Following treatment, her psychomotor function improved and weight was gained rapidly. The ceruloplasmin level was below normal at 13 months, 1.5 μmol/l (normal: 2-4.30), but it rose to normal after copper treatment. She suffered from amyotrophy and dysmetria, and had frequent respiratory infections until age 10. She is mentally retarded and attends a special school. Her development at 9 years corresponded to that of a 21/2-year-old. She has never been able to walk independently, but is able to move around on her bottom. At the age of 12 years, she has no language, but communicates using pictograms. Increased 64Cu uptake and retention in fibroblasts: 122 ng 64Cu/mg protein/20 hours and 60.2% retention, (normal: 11.5-26.7 ng uptake and 9.7-22.7% retention). Her maternal uncle suffered from classical MD and died at the age of 18 months.
Patient F4 (family, 9229). She is only mildly affected. She has a slightly high arched palate, narrow thorax and slightly dry skin. The hair is thick dark, not typical of MD patients. She was able to sit up at 9 months and to walk at 3 years. She had some problems with language and mild learning difficulties, for which she was at a special school. Copper treatment has never been given. At 11 years of age: Ceruloplasmin: 0.35 g/l (normal: 0.2-0.4 g/l) and S-Copper: 19 μmol/l (normal: 12-25 μmol/l) were normal. Increased 64Cu uptake performed on amniotic cells from 16th week of gestation, and on fibroblasts when she was 22 years old: 40.1 ng64Cu/mg protein/20 hours and 38.5% retention, (normal: 11.5-26.7 ng uptake and 9.7-22.7% retention). Her brother suffered from classical MD and died at the age of 8 months.
Patient F5 (family, 91284). She was able to sit up at 16 months, and to walk without support at 2 years. She could talk at 3 years, but has significant learning difficulties (IQ 64, 10 years old). Ceruloplasmin: 37.8 mg/dl (normal: 20-60 mg/dl) S-Copper: 114 μg/dl (normal: 60-180 mg/dl). The hair was brittle and sparse with pili torti. Her EEG was abnormal when she was 10 years old. Her mother has also mild learning difficulties. Her brother suffered from a slightly milder form of MD and died at the age of 7 years and 8 months.
Patient F6 (family, 92209). There were no early neonatal problems. She was subsequently noted to have short fine hair, a large fontanelle, and low muscular tone. The skin is dry and hypopigmented, and she has severe developmental delay. No copper treatment was given. Increased 64Cu uptake and retention in fibroblasts: 66.2 ng64Cu/mg protein/20 hours uptake with 45% retention, (normal: 11.5-26.7 ng uptake and 9.7-22.7% retention). Her brother suffered from classical MD and died at 21/2 years of age.
Patient F7 (family, 92283). She has severe mental and motor retardation. She had seizures until the age of 4. At the age of 41 years old she was in residential care. She is not able to walk. The hair is thin, fragile, and the skin dry. Her brother suffered from classical MD and died at 27 months. Slightly increased 64Cu uptake and retention in fibroblasts: 34 ng 64Cu/mg protein/20 hours and 30.7% retention, (normal: 11.5-26.7 ng uptake and 9.7-22.7% retention).
Patient F8 (family, 92292). She has blondish-brown hair that is moderately coarse. At the age of 14 years she was mildly mentally retarded. In addition, she had mild hypopigmentation and prominent areas of demarcated hypopigmentation all over her body but most pronounced over her abdomen, buttocks and left thigh. The vessels are tortuous. 64Cu uptake was normal but retention slightly increased: 22 ng 64Cu/mg protein/20 hours with 25-43% retention, (normal: 11.5-26.7 ng uptake and 9.7-22.7% retention). Her brother suffered from classical MD and died 25 months old. The mother and half-sister (F8-S1) are also carriers of the mutation in the ATP7A genes and have some signs of MD. The two sisters and the brother all have different fathers. The mother and the sister are both neurologically normal, but they both have some skin hypopigmentation, especially the sister who has also tortuous vessels, low serum copper and ceruloplasmin.
Patient F9 (family, 94228). She had mild psychomotor delay and was at the age of 29 years mildly mentally handicapped with an IQ of 83. At the age of 2 years, she suffered from convulsions. At the age of 13 she had skeletal changes (lumbosacral lordosis, genu valgum, flat feet, arachnodactyly), and ataxia. The 64Cu uptake in fibroblasts was slightly increased: 28.4 ng 64Cu/mg protein/20 hours and a clearly increased retention: 33.5% (normal: 11.5-26.7 ng uptake and 9.7-22.7% retention). No treatment was given. Her brother suffered from classical MD but received copper treatment and lived until the age of 71/2 years. At the age of 29 years she had a "professional capacities certificate" and is working. Her sister (F9-S1), also a carrier of the mutation, has mild symptoms, with an IQ slightly below normal.