Abstracts A55

intractable epilepsy, but dysmorphic symptoms are mild or absent. Only small 15q duplications, which do not include PWACR may have a normal phenotype. In our case, as in other cases with ‘large’ duplication, the duplicated zone also contains the GABA receptor subunit gene cluster. It may be postulated that an abnormal dosage of this gene (duplicated in this case, deleted in Angleman syndrome) may play a role in generalized epilepsy.

397 The clinical phenotype of a child with a novel calcium channel gene (CACNAl A) mutation associated with episodic ataxia type 2 and absence epilepsy S M ZUBERI,’ L H EUNSON,’ M G HANNA,’ J B P STEPHENSON,’ V RAMESH3 ‘Fraser of A/lander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK; ‘Clinical Neurology, Institute of Neurology, Queen Square, London, UK; 3Paediatric Neurology, Newcastle General Hospital, Newcastle, UK

Objective: To report the clinical features of a child with a novel mutation in the human voltage-gated calcium channel gene CACNAlA.

Introduction: Mutations in the CACNAlA gene on chromosome 19~ are associated with the autosomal dominant disorders episodic ataxia type 2 (EA2) and the allelic familial hemiplegic migraine. Expansions of a CAG trinucleotide repeat within the gene cause spino- cerebellar ataxia type 6. Mutations in the homologous mouse gene may produce autosomal recessive pheno- types with ataxia and absence epilepsy.

Clinical phenotype: This 12-year-old boy had febrile and afebrile generalized tonic-clonic seizures starting at the age of 3 years. He has gone on to develop episodes of gait ataxia that may last from minutes to hours. The seizures may follow an ataxic episode or be unrelated. Interictally he has signs of cerebellar dysfunction with nystagmus on lateral, and vertical up or downgaze. He has failure to suppress his vestibular-ocular reflex with visual fixation and a variable degree of upper limb and gait ataxia. Video data are available for presentation. In recent years he has had absence seizures. Interictal EEG shows bursts of generalized polyspike and wave. MRI at the age of 10 was normal. His symptoms have not responded to various anti-epileptic drugs including acetazolamide.

Molecular genetic study: He has a heterozygous C to T transition at nucleotide 5733 resulting in R1820stop. This is not present in either parent or 100 controls tested and would be predicted to be pathogenic. It is the most distal truncation mutation identified in this gene.

Conclusion: This report expands the phenotype associated with mutations in the voltage gated calcium channel gene CACNAlA to episodic ataxia type 2 and epilepsy.

Section VII: Genetics and syndromes

190 Early onset Cockayne syndrome: Case report A ADAMI,’ M STEFANINI,‘T NARDO,’ R SANGERMANI,’ P VAGLIA’, E PIOZZI-’ ‘Divisione di fediatria, Ospedale San Carlo Borromeo, Milano, Italy; ‘Istituto di Genetica biochimica ed evoluzionistica CNR, Pavia, Italy; 3Divisione Oculistica Pediatrica Ospedale di Niguarda, Milano, Italy

Cockayne syndrome is a rare autosomal recessive disorder characterized by severe postnatal dwarfism, hypersensitivity to sunlight, microcephaly, senile appearance and progressive neurological dysfunction together with other symptoms and signs showing wide variations. Since it was first described in 1936 it has become apparent that it is a progressive disorder with an underlying leucodystrophy. Signs become evident in early childhood between 6 months and the first years of age. Although the underlying molecular defect is still unknown there is a clear evidence that DNA repair is affected. In cultured Cockayne syndrome fibroblasts, the failure of RNA synthesis to recover to normal rates after LJV-C irradiation provides a useful and relatively simple diagnostic test both pre- and postnatally.

An early onset ‘severe form’ of Cockayne syndrome has been reported in at least 20 patients. Prenatal onset growth deficiency, early postnatal congenital cataracts, severe neurological impairment and early deterioration characterize this condition. Death usually occurs by 6 or 7 years of age. We report here on clinical and biochemical analyses of one patient with extremely severe Cockayne syndrome. He was the third child of healthy, first-cousin parents coming from Sri Lanka. The mother had experienced one miscarriage. The first child died at 7 months of age with a severe growth deficiency (weight 3500 g). The second child, a girl 12 years old, is healthy.

Our patient was born after a normal term pregnancy. Weight at birth was 263Og, length 45 cm, and head circumference 30.5 cm. The growth was severely affected from the first month of life but he gained weight up to the age of 1 year when tube feeding was introduced with minimal success till the age of 2 years. Thereafter his weight remained static as did the length. A severe microcephaly was present at birth. After 12 months there was no further growth in the head circumference (39 cm). Bilateral cataracts was detected at 2 months. Severe neurological impairment was early detected. When he was 14 months old hypersensitivity of his skin to sunlight was noticed. A CT brain scan at 6 months of age showed mild cerebral atrophy, megacisterna magna but no calcifications. Calcifications of basal ganglia were detected on a CT scan when he was 4 years old. An MRI at 4 years of age showed cortical atrophy, periventricular and subcortical white matter lesions and severe atrophic involvement of the cerebellum. Laboratory investigations were normal except for a persistent hyperuricaemia and increased serum glutamic-oxaloacetic transaminase and glutamate pyruvate transaminase. UV-irradiated fibro- blasts showed a failure to recover a normal rate of RNA synthesis. By genetical analysis the patient was assigned to the complementation group B of CS. The infant died at 4 years 5 months of pneumonia.