Autism in patients with propionic acidemia

https://doi.org/10.1016/j.ymgme.2016.10.009Get rights and content

Highlights

  • Five out of twelve propionic acidemia patients with mutations in PCCB were diagnosed with ASD according to DSM criteria.

  • Abnormal neurodevelopment and recurrent lactic acidemia were common in fully compliant patients with propionic acidemia.

  • Global developmental delay might occur in NBS patients without any previous metabolic disarrangement.

  • Chronically decreased valine levels and increased leucine to valine ratios were measured in 60% of the patients.

  • Altered branch chain amino acid- and short chain fatty acid levels could represent a metabolic phenotype of autism.

Abstract

Certain inborn errors of metabolism have been suggested to increase the risk of autistic behavior. In an animal model, propionic acid ingestion triggered abnormal behavior resembling autism. So far only a few cases were reported with propionic acidemia and autistic features. From a series of twelve consecutively diagnosed cases with propionic acidemia, we report on eight patients with autistic features.

The patients were followed 2–4 times a year and underwent regular clinical, dietary and laboratory investigations. Psychological evaluation was performed every second to fourth year.

All patients were compliant with the standard diet and carnitine supplementation. None of the patients had frequent metabolic decompensations. From the metabolic factors known to impact neuropsychological outcome we detected chronically decreased valine levels and altered valine to leucine ratios in five out of the eight patients. Recurrent lactic acid elevations were present in six out of the eight patients. Five of the eight patients were diagnosed with Autism Spectrum Disorder, four of them had pathogenic variants in PCCB. Disorder according to DSM-IV and/or DSM-5 criteria. One of the patients diagnosed with propionic acidemia by newborn screening had the most significant behavioral features and another was diagnosed with Autism Spectrum Disorder prior to propionic acidemia.

We hypothesize that chronic suboptimal intracellular metabolic balance may be responsible for the increased risk for autistic features in propionic acidemia. We propose that patients diagnosed with propionic acidemia should be screened for Autism Spectrum Disorder.

Introduction

Propionic acidemia (PA) is a severe organic acidemia, characterized by acute episodes of metabolic acidosis, ketosis, lactic acidemia, hyperammonemia, lethargy, basal ganglia involvement, and seizures. Even well treated patients might develop growth delay, developmental and speech delay. Long term outcome is often characterized by intellectual disability [1], [2]. Recurrent episodes of pancreatitis, muscle weakness and metabolic cardiomyopathy occur in a high percentage of cases, especially in those with insufficient therapeutic compliance [3]. Even the most adequately treated patients might develop neurologic symptoms including psychomotor retardation, speech delay, dystonia and even ischemic strokes of the basal ganglia [2]. Behavioral changes are relatively common in adolescent patients with PA, though Autism Spectrum Disorder (ASD) has been only reported in a single patient.

ASD is a complex neurodevelopmental disorder, characterized by social impairments, communication difficulties, and restricted, repetitive, and stereotyped patterns of behavior. Several inborn errors of metabolism have been described as increasing a patient's risk for ASD, including lysosomal storage diseases, disorders of the creatine synthesis, disorders of purine and pyrimidine metabolism or dysfunction of the urea cycle, but autistic features are not frequently reported in organic acidemias [5], [8], [9], [10], [11]. With the growing frequency of patients being diagnosed with ASD, sometimes it is difficult exclude a coincidental diagnosis of autism in certain metabolic conditions from comorbidity, especially in case of intellectual disability. The incidence of metabolic disorders in autistic patients is not known, but is estimated as high as 5%, while in the general population cumulative occurrence of inborn errors of metabolism is closer to 1 in 8005. In recent guidelines for the treatment of propionic acidemia, evaluation and monitoring for autism is not yet included [2].

Interestingly, studies evaluating the effects of elevated propionic acid in rats have suggested a possible connection with autism [6], [7]. Propionic acid administered systemically or by intracebro-ventricular injection to adult rats produced a rapid induction of repetitive movements, hyperactive activity, and seizure activity along with neuro-pathological and biochemical similarities to human ASD [6]. The mechanisms by which elevated levels of propionic acid affect the CNS are unknown, but possible candidates include interference with cellular metabolism, increased inflammatory cytokines and the reduction of intercellular gap-junctional communication.

Here we report on eight patients with autistic features and propionic acidemia from a case series of twelve consecutively diagnosed propionic acidemia patients. Biochemical and clinical information was collected and evaluated whether a risk factor for autism could be found.

Section snippets

Patient selection

A total of eight patients with propionic acidemia (PA) were evaluated in detail in this study. The inclusion criteria were the biochemical diagnosis of propionic acidemia confirmed in fibroblasts, in two centers, between 1995 and 2015. Twelve patients were diagnosed during the twenty years period. Four patients were excluded from the data analysis due to the unavailability of sufficient detailed clinical/metabolic and behavioral data. The patients' age range was between 3 and 20 years, with a

Clinical course and prognosis

Of the twelve patients we studied, eight had sufficient information for this retrospective study. These were also the patients who showed autistic features. Of these eight patients five were diagnosed in the neonatal period. Four presented with positive newborn screens and minimal symptoms. One had clinical symptoms before newborn screening results. The remaining 3 patients presented between 2.5 months and three years with symptoms of a metabolic coma and were clinically diagnosed (Table 1).

Discussion

While the etiologic factors in most patients with symptoms in the autistic disorder spectrum are not fully understood, changes in amino acid metabolism and organic acid concentrations have been reported in animal models mimicking autistic symptoms [6], [7]. Furthermore, amino acid levels in autistic patients have been reported as significantly different from non-autistic control groups [3], [5], [14]. Inborn errors of metabolism such as propionic acidemia have been suggested to increase the

Acknowledgements

P.W. is supported by the Clinical Research Foundation of University Hospitals Leuven 2015, Leuven, Belgium. M.B. is supported by RADIZ, Rare Disease Initiative Zurich, a clinical research priority program of the University of Zurich.

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