In 1995, a consensus statement was published for the purpose of summarizing the salient clinical features of Angelman syndrome (AS) to assist the clinician in making a timely and accurate diagnosis. Considering the scientific advances made in the last 10 years, it is necessary now to review the validity of the original consensus criteria. As in the original consensus project, the methodology used for this review was to convene a group of scientists and clinicians, with experience in AS, to develop a concise consensus statement, supported by scientific publications where appropriate. It is hoped that this revised consensus document will facilitate further clinical study of individuals with proven AS, and assist in the evaluation of those who appear to have clinical features of AS but have normal laboratory diagnostic testing.

Alcohol-responsive myoclonic dystonia is reported in 26 individuals in a six-generation family, thus indicating autosomal dominant inheritance. Twenty affected family members aged between 3 and 56 years were examined on one occasion. Myoclonus in arms, shoulder, and neck distribution was seen in 17, with occasional generalized jerks in 14. Leg dystonia/hemidystonia was seen in two infant cases, writer's cramp in seven, torticollis/retrocollis in two, and finger tremor in three. The onset of myoclonus was regularly reported from 2 to 3 years of age, the onset of leg dystonia/hemidystonia from 6 to 18 months of age, writer's cramp from early school age, and neck dystonia from late teenage. The effect of alcohol had been noted in 10 individuals, and seven of them abused alcohol. Once established, the neurological signs did not progress significantly. Leg dystonia resolved in two juvenile members. Two adult members had recovered from myoclonus: one elderly man and one posthemorrhagic spastic hemiplegic man. Extensive family investigation is necessary to clarify the clinical variation of this autosomal dominant disorder of involuntary movements.

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.

In a nation-wide survey of Aicardi syndrome, defined as the onset of epilepsy in the first six months of life, agenesis of the corpus callosum (partial or total) and lacunar chorioretinopathy, 18 patients, all girls, born between 1975 and 2002 were identified in Sweden. Fifteen were definite cases and three were regarded as probable, since they only fulfilled two of three inclusion criteria in addition to other cerebral malformations and/or chorioretinal changes. Calculations based on this survey and population-based studies on epilepsy in retarded children yielded a prevalence rate in the range of 2 - 15 : 100 000 girls. All but one had an ordinary birth weight, length and head circumference for gestational age. One was born preterm, one post term. The age at diagnosis varied from three days to 12 years and decreased during the period reflecting the increased awareness of the syndrome. Eleven came to medical attention because of seizures. Six had myoclonic, four generalized tonic-clonic and eight tonic, clonic or complex partial seizures. One had hypsarrhythmia, five multifocal epileptiform activity, three bilateral independent bursts, two burst-suppression pattern, six other types of spikes and one slowing of background activity. Asymmetrical EEG abnormalities indicating independent hemispheric dysfunction were detected in 13/18 (72 %). Complete absence of the corpus callosum was found in 13/18 (72 %), although not identical with the previous group, a partial defect in 3/18 (17 %), and a thinning in 2/18 (11 %). Of 15 children with definite Aicardi syndrome, 13 had binocular and two monocular lacunae. In one of the latter two, subtle monocular lacunae were found on fundus photographs, but had been missed on repeated clinical examinations. Of three children with probable Aicardi syndrome typical lacunae were reported in one and other kinds of depigmentation in the other two. Most of the children had anomalous optic discs. Neuroimaging in infancy or early childhood combined with ophthalmological examination and ocular fundus photography will facilitate an early diagnosis of Aicardi syndrome. Seizure type and EEG abnormalities may be non-specific at onset.

We report on three patients with MeCP2 mutation and male Rett phenotypes. Two brothers with T158M mutations and normal karyotype had a severe early onset encephalopathy, progressive microcephaly, severe feeding problems, breathing and sleep disturbances. They died at the ages of 1 year and 8 months, and 3 years and 1 month. This mutation has previously been reported in three males. The phenotypes show a strong resemblance, and might in fact represent a clinical-genetic entity of the T158M mutation within the complex of congenital encephalopathies in males with MeCP2 mutations. We also report a 3-year-old boy with a R294X mutation, normal karyotype, and a more protracted course. He was inactive and sucked poorly from start. The head growth decelerated from the age of 6 months and the feeding problems increased requiring gastrostomy. He had a rapid deterioration period at 2 years and lost sitting and hand grasping functions. He had prolonged periods with tremor and epileptic myoclonus, shifting tonus, and dystonic extension of the trunk and legs, bruxism, and irregular breathing. He was clinically stable with preserved visual and emotional contact function by the age of four years. None of the boys had dysmorphic features.