Peter Burgard

A European multicenter study of phenylalanine hydroxylase deficiency: Classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.

Diagnosis and management of glutaric aciduria type I - revised recommendations

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.

Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.

Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of l-lysine, l-hydroxylysine, and l-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n = 218) or presymptomatically by neonatal screening (n = 23), high-risk screening (n = 24), or macrocephaly (n = 14). Most symptomatic patients (n = 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with l-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.

Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB).

Isolated methylmalonic acidurias comprise a heterogeneous group of inborn errors of metabolism caused by defects of methylmalonyl-CoA mutase (MCM) (mut0, mut–) or deficient synthesis of its cofactor 5′-deoxyadenosylcobalamin (AdoCbl) (cblA, cblB). The aim of this study was to compare the long-term outcome in patients from these four enzymatic subgroups. Eighty-three patients with isolated methylmalonic acidurias (age 7–33 y) born between 1971 and 1997 were enzymatically characterized and prospectively followed to evaluate the long-term outcome (median follow-up period, 18 y). Patients with mut0 (n = 42), mut− (n = 10), cblA (n = 20), and cblB (n = 11) defects were included into the study. Thirty patients (37%) died, and 26 patients survived with a severe or moderate neurologic handicap (31%), whereas 27 patients (32%) remained neurologically uncompromised. Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF. Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut− and cblA defects. In addition, long-term outcome was dependent on the age cohort and cobalamin responsiveness.

Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

SummaryGlutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns. Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography–mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines. Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood. The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia. During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency. Maintenance treatment consisting of a diet combined with oral supplementation of L-carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients. This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients. Therefore, GCDH deficiency is now considered to be a treatable condition. However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients. At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.

Use of guidelines improves the neurological outcome in glutaric aciduria type I

To evaluate the effect of treatment according to current evidence‐based recommendations on the neurological outcome of patients with glutaric aciduria type I (GA‐I).

Sustained attention in adult phenylketonuria : the influence of the concurrent phenylalanine-blood-level

The effect of concurrent phenylalanine levels (Phe-level) on sustained attention was tested in a group of 19 early treated adult PKU patients. Mean age was 20.5 years; WAIS IQs were in the normal range (M = 109.3). Phe-levels were manipulated in a high-low-high design by reintroduction of a strict phenylalanine-reduced diet for 4 to 5 weeks between test time 1 and 2 and returning to usual diet between test time 2 and 3. A control group of 20 healthy subjects, mean age 20.7 years was tested twice. Results of a sustained attention task are presented. In adult PKU patients with high concurrent Phe-levels, sustained attention is significantly impaired and reaction times are prolonged. In the low Phe-level condition, performance improved significantly. Nevertheless, the PKU group did not reach the level of performance of the control group. Results are not influenced by IQ and suggest a sustained attention deficit in adult PKU patients that varies according to the concurrent Phe-level. The partial reversibility of the deficits provides support for the hypothesis that biochemical mechanisms rather than structural changes of the brain underlie the relationship between concurrent Phe-level and sustained attention.

The reality of dietary compliance in the management of phenylketonuria

In phenylketonuria (PKU), it is common for blood phenylalanine (Phe) concentrations to be outside optimal target ranges, particularly in teenagers and adults, indicating inadequate compliance. It is well known that significant noncompliance exists, and the situation in PKU would appear no different than other chronic conditions. In PKU, compliance is complex, being subject to diverse definitions, and factors influencing compliance include the nature and nurture of the patient, as well as the inconvenience, cost and availability of dietary treatment. It is also a dynamic process, with many patients changing between a state of compliance and partial and noncompliance. In PKU, compliance has received little rigorous study, and there have been few observational reports identifying barriers and behaviors impacting dietary compliance. Compliance assessment measures remain inadequately defined. The direct assessment of blood Phe concentration is perhaps the best overall measure, but there is no universal agreement about the number of Phe concentrations that should be within target range and frequency or timing of measurement. Although no one strategy for improving compliance is universally effective, and an individualized approach to noncompliance is essential, it is important to have clear evidence about the most effective strategies in achieving long-term dietary adherence in PKU.

Development of intelligence in early treated phenylketonuria.

Abstract Designs, analyses and results of longitudinal studies of intelligence of patients treated early for phenylketonuria (PKU) are reviewed. All studies converge on the conclusion that after the age of 10 years, IQ development is stable for different degrees of dietary relaxation. On average, for each 300 μmol/l increase in blood phenylalanine (Phe) levels pre-school, IQ decreases by about half a standard deviation. Children with Phe levels below 400 μmol/l in early and middle childhood had the best outcomes which were near normal. PKU seems to suppress the global level of IQ without impairment of domain-specific competencies. For historical reasons there is no research on IQ development of early treated patients in middle or late adulthood, and it remains unclear whether older age groups might carry new risks. Conclusion It is argued that control group designs, meta-analysis, and interdisciplinary studies combining psychology, neurology and neuropathology could increase the understanding of phenylketonuria as well as the scientific basis of its treatment.

Neuropsychologic Functions of Early Treated Patients with Phenylketonuria, on and off Diet: Results of a Cross-National and Cross-Sectional Study

Twenty-two French patients with early treated phenylketonuria (PKU) off diet (no reduced phenylalanine, Phe) since their 5th birthday, 23 German patients on diet (reduced Phe), and 21 healthy control subjects from childhood to adulthood matched for age, sex, and IQ were investigated for visuomotor reaction time, sustained attention, and visual stimulus scanning. Determinations were made whether 1) the three groups showed different developmental trends in their reaction times, 2) the threshold of a Phe blood level of 360 μmol/L formulated in recent recommendations can be regarded as safe, 3) test performances are related to the quality of dietary control in the same way for all age groups, and 4) long-term elevated Phe levels result in aggravating effects of increasing differences between patients on and off diet and healthy controls. Results revealed that developmental trends were similar in all treatment groups. Only children with a mean Phe level below 360 μmol/L performed as well as control subjects. Differences between treatment groups decreased in adulthood, and no aggravating effect could be observed. Mean performance of patients with mild PKU off diet was in the same range as performance of patients with classical or mild PKU on diet, calling into question the benefit of treating these patients. It is concluded that it is preferably safer to maintain Phe blood levels below 360 μmol/L at least during the first 10 y of life.