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.

Beta-ureidopropionase deficiency presenting with congenital anomalies of the urogenital and colorectal systems.

Beta-ureidopropionase deficiency (McKusick 606673) is an autosomal recessive condition caused by mutations in the UPB1 gene. To date, five patients have been reported, including one putative case detected through newborn screening. Clinical presentation includes neurological and developmental problems. Here, we report another case of beta-ureidopropionase deficiency who presented with congenital anomalies of the urogenital and colorectal systems and with normal neurodevelopmental milestones. Analysis of a urine sample, because of the suspicion of renal stones on ultrasound, showed strongly elevated levels of the characteristic metabolites, N-carbamyl-beta-amino acids. Subsequent analysis of UPB1 identified a novel mutation 209 G>C (R70P) in exon 2 and a previously reported splice receptor mutation IVS1-2A>G. Expression studies of the R70P mutant enzyme showed that the mutant enzyme did not possess any residual activity. Long-term follow-up is required to determine the clinical significance of the beta-ureidopropionase deficiency in our patient.

Cardiac manifestations in oxidative phosphorylation disorders of childhood.

OBJECTIVE: To determine the frequency, type, and severity of cardiac involvement in pediatric patients with oxidative phosphorylation (OXPHOS) disorders. STUDY DESIGN: Retrospective review of clinical and laboratory records of all patients with definitive OXPHOS disorders diagnosed and treated at the Royal Children's Hospital in Melbourne between 1984 and 2005. RESULTS: Of a total of 89 patients (male:female ratio 1.5:1) 29 (33%) had cardiac involvement: 9 as presenting symptoms, 9 developing on follow-up, and 11 with subclinical cardiac findings. Leigh or Leigh-like syndrome and complex I and combined complex I, III, and IV deficiencies were the most common clinical and laboratory diagnoses, respectively. Clinically symptomatic patients had hypertrophic cardiomyopathy (5 patients), dilated cardiomyopathy (4 patients), combined ventricular hypertrophy and systolic dysfunction (3 patients), and left ventricular noncompaction (3 patients) at first assessment. A change in the type of cardiomyopathy was noted on follow-up in 2 patients. Conduction and rhythm abnormalities were present in 7 symptomatic patients. CONCLUSIONS: Cardiac assessment in children with OXPHOS disorders may reveal subclinical abnormalities of cardiac function. Patients who present with primary cardiac features have a poor prognosis. OXPHOS disorders should be considered in the differential diagnosis of children presenting with otherwise unexplained cardiomyopathy.

VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis.

We diagnosed six newborn babies with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) through newborn screening in three years in Victoria (prevalence rate: 1:31,500). We identified seven known and two new mutations in our patients (2/6 homozygotes; 4/6 compound heterozygotes). Blood samples taken at age 48-72 h were diagnostic whereas repeat samples at an older age were normal in 4/6 babies. Urine analysis was normal in 5/5. We conclude that the timing of blood sampling for newborn screening is important and that it is important to perform mutation analysis to avoid false-negative diagnoses of VLCADD in asymptomatic newborn babies. In view of the emerging genotype-phenotype correlation in this disorder, the information derived from mutational analysis can be helpful in designing the appropriate follow-up and therapeutic regime for these patients.