- Case report
- Open Access
- Open Peer Review
Co-existence of Phenylketonuria and Fabry disease on a 3 year-old boy: case report
© Concolino et al; licensee BioMed Central Ltd. 2010
- Received: 16 January 2010
- Accepted: 17 May 2010
- Published: 17 May 2010
The co-existence of two genetically distinct metabolic disorders in the same patient has rarely been reported. Phenylketonuria (PKU) is an inborn error of the metabolism resulting from a phenylalanine hydroxylase deficiency. Fabry disease (FD) is an X-linked lysosomal storage disorder due to a deficiency of the enzyme alpha-galactosidase A.
We report a case of a 3 year- old boy affected by classic PKU and FD, both confirmed by molecular data. The FD was suspected at the age of 21 months on the presence of non-specific GI symptoms (severe abdominal pain and periodically appearance of not specific episodes of gastroenteritis) apparently non related to PKU.
This is the first report of co-existence of FD and PKU, two different congenital inborn of metabolism and in consideration of the prevalence of each disease this chance association is a very unusual event. The co-existence of this diseases made very difficult the correct interpretation of clinical symptoms as lack of appetite, severe abdominal pain and non-specific gastroenteritis episodes. Furthermore, this case report helps to define the early clinical phenotype of FD.
- Enzyme Replacement Therapy
- Fabry Disease
- Faecal Occult Blood Test
- Severe Abdominal Pain
The presence of two genetically distinct metabolic diseases in the same patient has rarely reported. Phenylketonuria (PKU) (OMIM 221600) is inborn error of the metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH). The Phenylalanine (Phe) hydroxylase gene is located on chromosome 12q22-q24.1 and so far more than 400 different mutant Phe hydroxylase alleles have been described. A Phe restricted diet can improve the effects of high serum Phe on cognitive functions. Fabry disease (FD) (OMIM 301500) is an X-linked lysosomal storage disorder due to a deficiency of the enzyme alpha-galactosidase A (GLA). The GLA gene maps at Xq22.1 and more than 400 mutations have been recorded in the Human Gene Mutation Database . The disease affects kidney, myocardium, central nervous system, heart, ears, eyes, skin and, in many patients, the gastrointestinal tract (GI) . FD can become clinically manifest in childhood with chronic neuropathic pain, hypohidrosis/hyperhidrosis, angiokeratoma, acroparaesthesiae, non-specific GI symptoms and hearing problems . Recently, recombinant enzyme replacement therapy (ERT) has become available. The diagnosis of FD is often delayed in the pediatric population. The symptoms may appear in a nonspecific pattern in this age group, and often many years are required to identify the underlying nature of the complaints. Pedigree studies and a careful family history are important and in the absence of such information, the diagnosis of FD, confirmed by enzyme/genetic analysis, is usually suspected on the basis of strong clinical signs and recognition of the peculiarity of the clinical findings . We report a new pediatric case of FD with early GI involvement in a 3- year-old boy affected by PKU.
The diagnosis was confirmed by the reduced plasma a-galactosidase A (0,32 nmol/h/ml), decreased activity assayed in leucocytes [0,65 nmol/mg.prot/h (normal range: 26-80)] and the molecular analysis of GLA gene documented the hemizygous missense mutation g.5234G>A 2 in the exon 2 that changes in the protein Arg with Hys (p.R112H). In the mother, the mutation analysis showed that she carries the same heterozygous mutation. We performed a systematic pedigree analysis by the assay of GAL activity in the family and mutation analysis to brothers, sisters, nephews of the mother that resulted normal. The grandmother (II.2) and a brother (III.1) of the mother refused to undergo to molecular analysis (Fig. 1).
Due to the lack of other clinical signs we decided not to start ERT but to perform a clinical follow-up every 6 months. Today the patient is 5-year-old, continues a diet therapy for PKU and severe abdominal pain is present periodically without triggering factors in absence of other symptoms.
The clinical relevance of this case is the combination of two different metabolic inherited diseases and the early presentation of FD. The co-existence of PKU and FD made very difficult the correct interpretation of clinical symptoms as lack of appetite, severe abdominal pain and non-specific gastroenteritis episodes. In fact GI symptoms and feeding problems also in young PKU children are present . Non specific enteropathy has been reported in about 80% of pediatric FD patients4 and these symptoms must alert pediatricians to possible FD, also because the incidence of the disease seems higher than previously estimated . It is, therefore, difficult predicting the clinical outcome in this young patient who is still free of organ involvement. The mutation p.R112 H found in our patient has been previously identified in patients with either the classic phenotype or the cardiac-variant phenotype . Given that the reversibility of disease progression in adulthood is limited, early ERT appears reasonable, because the disease progresses with age. However, the optimum time to start ERT in order to prevent end-stage organ damage is also unknown. It is possible that beginning of therapy at an early age, before the occurrence of significant organ damage and dysfunction, produces better clinical results. Moreover, little is known about the natural history of the disease in childhood, and systematic prospective data on the clinical manifestations of FD by ERT in the pediatric population are not available. It is essential, however, to study the therapeutic and possibly preventive effects of this treatment approach on children in a controlled way. Clinical trials are currently underway to evaluate the safety and efficacy of enzyme replacement therapy in children with FD . According to current expert recommendations, ERT in male patients should ideally be provided in the second decade of life or as soon as clinical signs and symptoms, such as left ventricular hypertrophy, proteinuria, hypoidrosis or pain, are observed . Further, based on our knowledge, cases of FD and PKU have been never described in the same patient. Finally, this case emphasizes the need to look for the coexistence of other inherited metabolic diseases when the clinical history is not completely consistent with the well assessed first diagnosis.
Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
This study was not funded.
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