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Infantile spasms and Menkes disease Volume 2, numéro 4, Décembre 2000

Materials and methods

Case 1

A boy born in France, after a 36-37 weeks gestation. Pregnancy and delivery were uneventful. Birth weight was 3,120 g and length 48 cm. The Apgar score was normal. Family history was positive with four deceased maternal uncles who had suffered from Menkes disease, and the mother of our patient presenting with an intellectual handicap.

During the first days of life the diagnosis of Menkes disease was suspected on the basis of family history, lethargy and hypotonia. Serum copper and ceruloplasmin levels were very low, as well as the CSF copper. Serum and CSF lactate were increased (table I).

Pili torti was confirmed microscopically. Skeletal X-ray films showed widening of the flared metaphysis with spiky protrusions at the edges of humerus and radius bones. Wormian bones were seen in the skull. The first EEG performed at the age of 38 days of life was normal.

On the MRI angiography and Doppler Ultrasound (figure 1) the cerebral vessels were markedly elongated and tortuous. There was no abnormal myelinisation.

A muscle biopsy stained by inmunohistology showed cox negative fibres, indicating the probability of a cytocrome c oxidase deficiency. A spectrophotometric analysis of the respiratory chain was normal. The Cu64-uptake was increased, and the genetic study demonstrated a deletion of exon 22. Treatment with subcutaneous injections of copper-histidine was introduced at 45 days of life.

At the age of 3 months and despite ongoing copper therapy, the boy developed infantile spasms occurring in series. The interictal EEGs showed a slow and asymmetric background activity with multifocal spikes and slow wave discharges. Vigabatrin was introduced.

Case 2

A boy born in France. Family history was negative. Pregnancy and delivery were normal. At the age of 5 months he presented infantile spasms, between 1 to 3 series of jerks every day, associated with developmental regression. Clinical examination revealed marked hypotonia, sparse and brittle hair and a bilateral pyramidal syndrome. Microscopic examination showed typical pili torti.

Serum copper, ceruloplasmin and CSF copper were decreased (table I). The Cu64-uptake of culture fibroblasts was significantly increased. The interictal EEGs showed no physiological organisation. The tracing showed bilateral slow waves, with posterior spikes. Two series of flexion spasms, lasting 10 minutes each, were recorded (figure 2).

Muscle biopsy showed a normal spectrophotometric analysis of the respiratory chain.

Angio-MRI revealed cortico-subcortical atrophy, diffuse abnormalities of the white matter with lacunar lesions (figure 3) and tortuous intracranial vessels (figure 4).

The molecular study of the ATP7A gene showed a mutation Ala629Pro (GCT => CCT) in exon 8. Treatment with subcutaneous copper-histidine was started immediately as well as vigabatrin therapy.

Results

Biochemical findings (table II). Serum copper and ceruloplasmin concentrations were measured every 15 days. In both cases, copper and ceruloplasmin levels returned to the normal range within 4 weeks following copper-histidine injections. A reduction of increased lactate levels in serum and in CSF was observed in case 2.

Clinical outcome. Contact with the examiner improved with therapy in both cases but axial hypotonia, pyramidal tract syndrome and failure to thrive persisted.

Our first patient (case 1) developed infantile spasms at the age of 3 months despite the ongoing treatment with copper-histidine and previous normalisation of biological values.

Spasms were one of the presenting symptoms in case 2. They did not improve clinically and electrophysiologically on copper-histidine therapy. Vigabatrin was discontinued and replaced by Nitrazepan at a dose of 0.3 mg/kg/day. A reduction in the frequency of infantile spasms was observed but the EEGs remained abnormal.

Management of infantile spasms was very difficult in both our cases.

Discussion

Seizures are often described in the literature as one of the most common symptoms of Menkes disease. However, a description of the type of seizures is not provided.

Hypsarrhythmia, as one of the EEG patterns, is mentioned in only a few articles, as well as slow or asymmetric background, multifocal spikes and slow waves discharges [9, 10].

Kreuder [11] reported a patient with Menkes disease who developed infantile spasms with typical hypsarrhythmia when dose levels of copper-histidine therapy were reduced. Increase of dose levels to previous levels was followed by an obvious but limited benefit in seizure control. White et al. [9] suggested that in some patients with Menkes disease, cerebral electrical activity may be influenced by the level of circulating copper.

Concerning onset of seizures, our cases suggest that there is no relation between biochemical parameters, initiation of treatment with copper-histidine and age at onset of infantile spasms. Copper-histidine treatment allowed normalisation of CSF copper in case 1 and serum copper and ceruloplasmin in both cases after four weeks of therapy. Our observations indicate that infantile spasms can be a presenting or late feature of Menkes disease and may not be amenable to therapy with copper-histidine.

Received August 17, 2000 / Accepted November 28, 2000