Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy.

BACKGROUND: Enzyme replacement therapy (ERT) for infantile-onset Pompe disease has been commercially available for almost 10 years. We report the experience of its use in a cohort treated at three specialist lysosomal treatment centres in the UK. METHODS: A retrospective case-note review was performed, with additional data being gathered from two national audits on all such patients treated with ERT. The impact on the outcome of various characteristics, measured just prior to the initiation of ERT (baseline), was evaluated using logistic regression. RESULTS: Thirty-three patients were identified; 13/29 (45%) were cross-reactive immunological material (CRIM) negative, and nine were immunomodulated. At baseline assessment, 79% were in heart failure, 66% had failure to thrive and 70% had radiological signs of focal pulmonary collapse. The overall survival rate was 60%, ventilation-free survival was 40% and 30% of patients were ambulatory. Median follow-up of survivors was 4 years, 1.5 months (range 6 months to 13.5 years). As with previous studies, the CRIM status impacted on all outcome measures. However, in this cohort, baseline failure to thrive was related to death and lack of ambulation, and left ventricular dilatation was a risk factor for non-ventilator-free survival. CONCLUSION: The outcome of treated patients remains heterogeneous despite attempts at immunomodulation. Failure to thrive at baseline and left ventricular dilation appear to be associated with poorer outcomes.

Reversal of respiratory failure in both neonatal and late onset isolated remethylation disorders.

Respiratory failure is a well-documented potential presentation of inherited isolated remethylation disorders (IRDs). It appears to be a combination of both central and peripheral neuropathy and has previously often been considered to herald an irreversible neurological decline. We present three patients, one with methionine synthase (cblG) and two with methyltetrahydrofolate reductase deficiency (MTHFR). One patient with MTHFR presented in infancy, and other patients in later childhood. All three patients required intubation for respiratory failure but in all three, this was totally reversed by the initiation of medical therapy. This consisted of betaine and folinic acid supplementation in all three, methionine in two and cobalamin supplementation in two. The rate of respiratory improvement was variable, though two of the cases were successful extubated within a week of commencement of medical therapy. We document their subsequent clinical, biochemical and electrophysiological progress and review the potential pathological mechanisms underlying respiratory failure in these disorders.

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.