First Case Report of Primary Carnitine Deficiency Manifested as Intellectual Disability and Autism Spectrum Disorder

Abstract

Systemic primary carnitine deficiency (PCD) is a genetic disorder caused by decreased or absent organic cation transporter type 2 (OCTN2) carnitine transporter activity, resulting in low serum carnitine levels and decreased carnitine accumulation inside cells. In early life, PCD is usually diagnosed as a metabolic decompensation, presenting as hypoketotic hypoglycemia, Reye syndrome, or sudden infant death; in childhood, PCD presents with skeletal or cardiac myopathy. However, the clinical presentation of PCD characterized by autism spectrum disorder (ASD) with intellectual disability (ID) has seldom been reported in the literature. In this report, we describe the clinical features of a seven-year-old girl diagnosed with PCD who presented atypical features of the disease, including a developmental delay involving language skills, concentration, and attention span, as well as autistic features and brain alterations apparent in magnetic resonance imaging. We aim to highlight the difficulties related to the diagnostic and therapeutic approaches used to diagnose such patients. The case reported here presented typical signs of PCD, including frequent episodes of hypoglycemia, generalized muscle weakness, decreased muscle mass, and physical growth deficits. A molecular genetic study confirmed the definitive diagnosis of the disease (c.1345T>G (p.Y449D)) in gene SLC22A5, located in exon 8. PCD can be accompanied by less common clinical signs, which may delay its diagnosis because the resulting global clinical picture can closely resemble other metabolic disorders. In this case, the patient was prescribed a carnitine-enriched diet, as well as oral carnitine at a dose of 100 mg/kg/day. PCD has a better prognosis if it is diagnosed and treated early; however, a high level of clinical suspicion is required for its timely and accurate diagnosis.

Potential Role of L-Carnitine in Autism Spectrum Disorder

“…Systemic primary carnitine deficiency (SPCD) is a progressive autosomal disturbance connected with impaired carnitine uptake by plasmatic membranes because of a deficiency in the OCTN2 transporter, which is coded by the SLC22A5 gene (localized on the 5q31 chromosome). Heterozygous or homozygous deficiency of OCTN2 transporters may be an autism risk factor [ 100 , 101 ]. In early life, SPCD is usually recognized as a metabolic decompensation manifested by hypoketotic hypoglycemia; encephalopathy, frequently connected with liver enlargement; increased serum level of aminotransferases; hyperammonemia; cardiomyopathy; muscular weakness; changed intestinal peristalsis and repeated infections in early life.…”

Effects of l-Carnitine in Patients with Autism Spectrum Disorders: Review of Clinical Studies

“…Several case reports have argued that carnitine administration is beneficial for treating metabolic abnormalities in several genetic disorders with well-known causes which commonly associate ASD with other clinical manifestations [26,27,28,29,30,31,32] (Table 2).…”

“…Primary carnitine deficiency (PCD) can result in a wide of spectrum of clinical manifestations ranging from early episodes with life-threatening [35] to even asymptomatic presentations [36], including reports of isolated gastrointestinal symptoms [37] and mild developmental delay [38,39]. Guevara-Campos et al [27] recently described a case of an ASD girl with primary carnitine deficiency accompanied by intellectual disability, muscle weakness, and repeated episodes of hypoglycemia. After a diagnosis of PCD, the patient received carnitine (200 mg/kg/day) and a Vitamin B complex consisting of 50 mg each of vitamins B1 and B2, 15 mg of B3, 2 mg of B6, and 10 mg of B12), divided into two daily doses, because she did not eat fruit.…”

“…Several inborn errors of metabolism have been reported as increasing a patient’s risk for ASD, including lysosomal storage diseases, disorders of the creatine synthesis, disorders of purine and pyrimidine metabolism and dysfunction of the urea cycle, but autistic features are not frequently reported in organic acidemias [52,53,54]. In terms of genetic syndromes associated to ASD, data on carnitine administration has been reported for patients with TMLHE deficiency [30], with mitochondrial disorders and hyperlactacidemia [26], primary carnitine deficiency [27], propionic acidemia [31], and q4− syndrome [32]. However, carnitine was co-administered with other vitamins/cofactors, such as vitamin B groups and coenzyme Q10, in all these disorders (except in the report of the patient with TMLHE deficiency), and it is difficult to attribute the beneficial effects to carnitine alone.…”

“…In contrast, the study performed on a patient with TMLHE deficiency reported significant improvements in ASD symptoms after carnitine administration. Interestingly, in the other disorders, there was improvement in ID and in muscle tone and development but ASD symptom improvement was rather limited in some reports [26,27]. Interestingly, administration of the carnitine-derivative, l -acetyl-carnitine (20–50 mg/kg/day), has been shown to improved hyperactive behavior and the improvement of social behavior in young boys with fragile X syndrome, a genetic syndrome that also include as clinical manifestation, ASD [55,56,57], and further RCTs are needed to recommend the use of l -acetylcarnitine for ASD symptoms and other psychological alterations that characterize this genetic disorder [58].…”