Delayed diagnosis of phenylketonuria – a case report of two siblings

Abstract

Phenylketonuria (PKU), is an autosomal recessive condition affecting the amino acid metabolism. The UK National newborn screening programme was commenced in 1969 and PKU is one among the five conditions included in the screening programme. We present the case history of two siblings of a family with a delayed diagnosis of PKU. This case history highlights such an occurrence. PKU should be considered as an important differential in the diagnosis of adult patients with learning difficulties, seizures and behavioural problems. It would be prudent to instigate plasma and urine amino/organic acid analyses in adult patients with unexplained neuropsychological manifestations.

Introduction

Phenylketonuria (PKU, OMIM:#261600 ¹ ), is an autosomal recessive condition affecting phenylalanine metabolism. ² The incidence of PKU is 1 in 10,000 births (1 in 4500 in Northern Ireland). ³ The rate limiting step in phenylalanine to tyrosine conversion is catalysed by phenylalanine hydroxylase. ² Deficiency of this enzyme leads to the classical biochemical picture of an excess phenylalanine and low tyrosine levels seen in PKU. ² The circulating phenylalanine concentrations in classical PKU are generally 10-fold higher (more than 1200 µmol/L) than that of an unaffected person. ⁴ The excess phenylalanine is excreted in the urine as phenylpyruvic acid and phenyllactic acid. Neurological damage is strongly associated with untreated classical PKU ⁴ and the prognosis of patients treated early is significantly improved. Though the damaging agents have not been identified with confidence, this is probably due to a combination of factors, ⁵ including high phenylalanine levels blocking the ingress of other amino acids into neurons. This is the basis of supplementation with large neutral amino acids ⁶ (includes tyrosine, tryptophan, threonine, methionine, valine, isoleucine, leucine and histidine) which has become a standard practice now. Early instigation of phenylalanine restricted diet ameliorates the irreversible neurological manifestations associated with this treatable metabolic condition.^1,2,4 Nowadays, PKU is almost entirely diagnosed by the newborn screening programme. ³ Failsafe measures defined by the UKNSPC ⁷ (UK National Screening Programme Centre) are in place now to ensure all babies receive newborn screening. In the early years of screening, coverage was incomplete and tests less reliable meaning not all patients may have been identified. We present the case history of two brothers from a family, who were first diagnosed with PKU in their fourth decade.

Index case

A 40-year-old unmarried Caucasian male, was referred to the neurology clinic with new onset tonic clonic seizures. His medical history included a diagnosis of hay fever and mild to moderate learning difficulties. He was the second child born to parents of non-consanguinous marriage. He was born at full term by normal home delivery. As a child, he had a history of delayed mile stones and a preliminary diagnosis of learning difficulties had been made. He went to a special school and was able to read but not write. He lived with his parents who were his main carers and was self-caring, pleasant and able to do simplified daily tasks. At the age of 39 years, he suffered two episodes of grand mal seizures. A diagnosis of epilepsy was made and he was commenced on Lamotrigine. His general and systemic examination was unremarkable (except for the above-mentioned learning difficulties) with normal deep tendon reflexes and no obvious tremor on the outstretched hands. A CT (computerized tomography) scan of head done during this period was reported to be normal. His deteriorating epileptic control and the co-existent history of learning difficulties led to the consideration for plasma and urine amino acids screening. This confirmed an elevated plasma phenylalanine concentration of 1451 µmol/L (reference range: 65–160 µmol/L) and decreased tyrosine concentration of 48 µmol/L (reference range: 57–110 µmol/L) consistent with a diagnosis of PKU.

Case history of sibling

A 42-year-old brother of the above patient with learning difficulties was screened subsequent to a diagnosis of PKU in his younger brother. He was the first born child of the family described above and was a term baby delivered at the hospital. He was noted to have significant delay in milestones at the age of 18 months. He was referred to the cerebral palsy clinic and attended a special school due to his severe learning difficulties. He had no other significant medical problems. He was fully mobile, able to self-groom and feed without assistance. He attended regular day care sessions. His general and systemic examination was unremarkable otherwise except learning difficulties. Plasma amino acid analysis revealed an elevated phenylalanine concentration of 1670 µmol/L (tyrosine was 74 µmol/L).

Post-diagnosis of PKU

With the therapeutic window of opportunity in our patients being lost, counselling the affected family was challenging. A phenylalanine-restricted diet was contemplated initially in both the affected patients. However, it was not pursued further as the benefits of such a diet were uncertain. Restricted diet may help with aggressive behaviour but agitation/aggressive behaviour was not an issue in either of the siblings. Currently, our patients are still managed at the specialist adult inborn errors clinic for provision of continuity of care and to aid coordination of any future medical needs pertinent to the condition.

Discussion

The National newborn screening programme was commenced in the UK in 1969. ³ We have been unable to substantiate the exact cause for the delayed diagnosis of PKU in our patients. The area of coverage in the early years of newborn screening programme and the increased likelihood of false negative tests (for PKU) with older techniques are possible considerations that need to be ruled out. As with any screening test, both false positives ⁸ and false negatives have been described in PKU. We would like to highlight some salient features of our case history that pre-empted the publication. Firstly, a delayed diagnosis of PKU is not uncommon, particularly, in patients born before the screening era. Delayed diagnosis of PKU presenting with neurological dysfunction like spastic paraparesis, dementia and mental retardation has been reported.^9,10,11,12 To the best of our knowledge this is the first ever case report, with simultaneous, delayed adult diagnosis of PKU in two members of the same family. Significant difference in phenotype is well documented in untreated classical PKU patients with only subtle learning difficulties in 10% of patients.^4,13,14 Secondly, though the MRC (Medical research Council) recommends a lifelong dietary phenylalanine restriction, a more controlled relaxation is often seen in the adult patients due to poor compliance. ¹⁵ Recommencement of dietary measures has been recommended should there be further intellectual deterioration, learning difficulties and neuropsychological problems. ⁴ A restricted dietary repertoire was not commenced in our patients due to concerns about behavioural problems. Nevertheless, there may be a need for commencing dietary restriction should the epileptic control detoriate in the index case, though the evidence is still lacking. ¹⁶ Thirdly, PKU is still a leading cause of mental retardation in some countries ¹⁷ and its possibility needs to be contemplated in patients from countries with non-availability of newborn screening programmes. And lastly, the lack of awareness on inherited errors of metabolism (IEM) disorders has been suggested a likely cause for their under diagnosis in adult patients. ¹⁸ Our case history is therefore aimed at increasing awareness of IEM as a possible differential in the diagnosis of patients with neuropsychological manifestations.

Conclusion

There is need for consideration of IEM disorders to be causal in unexplained neurological findings. It would be prudent to instigate urine and plasma amino acid with urine organic acid and plasma acylcarnitine analyses in patients with unexplained neuropsychological manifestations. Though the therapeutic window for clinical improvement is lost in our patients, the identification of the underlying condition may avoid the need for any further expensive investigations and facilitate long-term follow-up at a specialist metabolic clinic.